Therapeutic compounds and compositions, and methods of use thereof

ABSTRACT

Compounds and salts thereof that are useful as JAK kinase inhibitors are described herein. Also provided are pharmaceutical compositions that include such a JAK inhibitor and a pharmaceutically acceptable carrier, adjuvant or vehicle, and methods of treating or lessening the severity of a disease or condition responsive to the inhibition of a Janus kinase activity in a patient.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. application Ser. No.15/984,747 filed on May 21, 2018, which claims the benefit of priorityto U.S. Application Ser. No. 62/640,865, filed Mar. 9, 2018, andInternational Patent Application No. PCT/CN2017/085276, filed May 22,2017, each of which is incorporated by reference herein in its entirety.

FIELD OF THE INVENTION

The invention relates to compounds that are inhibitors of a Januskinase, such as JAK1, as well as compositions containing thesecompounds, and methods of use including, but not limited to, diagnosisor treatment of patients suffering from a condition responsive to theinhibition of a JAK kinase.

BACKGROUND OF INVENTION

Cytokine pathways mediate a broad range of biological functions,including many aspects of inflammation and immunity. Janus kinases(JAK), including JAK1, JAK2, JAK3 and TYK2, are cytoplasmic proteinkinases that associate with type I and type II cytokine receptors andregulate cytokine signal transduction. Cytokine engagement with cognatereceptors triggers activation of receptor associated JAKs and this leadsto JAK-mediated tyrosine phosphorylation of signal transducer andactivator of transcription (STAT) proteins and ultimatelytranscriptional activation of specific gene sets (Schindler et al.,2007, J. Biol. Chem. 282: 20059-63). JAK1, JAK2 and TYK2 exhibit broadpatterns of gene expression, while JAK3 expression is limited toleukocytes. Cytokine receptors are typically functional as heterodimers,and as a result, more than one type of JAK kinase is usually associatedwith cytokine receptor complexes. The specific JAKs associated withdifferent cytokine receptor complexes have been determined in many casesthrough genetic studies and corroborated by other experimental evidence.Exemplary therapeutic benefits of the inhibition of JAK enzymes arediscussed, for example, in International Application No. WO 2013/014567.

JAK1 was initially identified in a screen for novel kinases (Wilks A.F., 1989, Proc. Natl. Acad. Sci. U.S.A. 86:1603-1607). Genetic andbiochemical studies have shown that JAK1 is functionally and physicallyassociated with the type I interferon (e.g., IFNalpha), type IIinterferon (e.g., IFNgamma), and IL-2 and IL-6 cytokine receptorcomplexes (Kisseleva et al., 2002, Gene 285:1-24; Levy et al., 2005,Nat. Rev. Mol. Cell Biol. 3:651-662; O'Shea et al., 2002, Cell, 109(suppl.): S121-S131). JAK1 knockout mice die perinatally due to defectsin LIF receptor signaling (Kisseleva et al., 2002, Gene 285:1-24; O'Sheaet al., 2002, Cell, 109 (suppl.): S121-S131). Characterization oftissues derived from JAK1 knockout mice demonstrated critical roles forthis kinase in the IFN, IL-10, IL-2/IL-4 and IL-6 pathways. A humanizedmonoclonal antibody targeting the IL-6 pathway (Tocilizumab) wasapproved by the European Commission for the treatment ofmoderate-to-severe rheumatoid arthritis (Scheinecker et al., 2009, Nat.Rev. Drug Discov. 8:273-274).

CD4 T cells play an important role in asthma pathogenesis through theproduction of TH2 cytokines within the lung, including IL-4, IL-9 andIL-13 (Cohn et al., 2004, Annu. Rev. Immunol. 22:789-815). IL-4 andIL-13 induce increased mucus production, recruitment of eosinophils tothe lung, and increased production of IgE (Kasaian et al., 2008,Biochem. Pharmacol. 76(2): 147-155). IL-9 leads to mast cell activation,which exacerbates the asthma symptoms (Kearley et al., 2011, Am. J.Resp. Crit. Care Med., 183(7): 865-875). The IL-4Rα chain activates JAK1and binds to either IL-4 or IL-13 when combined with the common gammachain or the IL-13Rα1 chain respectively (Pernis et al., 2002, J. Clin.Invest. 109(10):1279-1283). The common gamma chain can also combine withIL-9Rα to bind to IL-9, and IL-9Rα activates JAK1 as well (Demoulin etal., 1996, Mol. Cell Biol. 16(9):4710-4716). While the common gammachain activates JAK3, it has been shown that JAK1 is dominant over JAK3,and inhibition of JAK1 is sufficient to inactivate signaling through thecommon gamma chain despite JAK3 activity (Haan et al., 2011, Chem. Biol.18(3):314-323). Inhibition of IL-4, IL-13 and IL-9 signaling by blockingthe JAK/STAT signaling pathway can alleviate asthmatic symptoms inpre-clinical lung inflammation models (Mathew et al., 2001, J. Exp. Med.193(9): 1087-1096; Kudlacz et. al., 2008, Eur. J. Pharmacol. 582(1-3):154-161).

Biochemical and genetic studies have shown an association between JAK2and single-chain (e.g., EPO), IL-3 and interferon gamma cytokinereceptor families (Kisseleva et al., 2002, Gene 285:1-24; Levy et al.,2005, Nat. Rev. Mol. Cell Biol. 3:651-662; O'Shea et al., 2002, Cell,109 (suppl.): S121-S131). Consistent with this, JAK2 knockout mice dieof anemia (O'Shea et al., 2002, Cell, 109 (suppl.): S121-S131). Kinaseactivating mutations in JAK2 (e.g., JAK2 V617F) are associated withmyeloproliferative disorders in humans.

JAK3 associates exclusively with the gamma common cytokine receptorchain, which is present in the IL-2, IL-4, IL-7, IL-9, IL-15 and IL-21cytokine receptor complexes. JAK3 is critical for lymphoid celldevelopment and proliferation and mutations in JAK3 result in severecombined immunodeficiency (SCID) (O'Shea et al., 2002, Cell, 109(suppl.): S121-S131). Based on its role in regulating lymphocytes, JAK3and JAK3-mediated pathways have been targeted for immunosuppressiveindications (e.g., transplantation rejection and rheumatoid arthritis)(Baslund et al., 2005, Arthritis & Rheumatism 52:2686-2692; Changelianet al., 2003, Science 302: 875-878).

TYK2 associates with the type I interferon (e.g., IFNalpha), IL-6,IL-10, IL-12 and IL-23 cytokine receptor complexes (Kisseleva et al.,2002, Gene 285:1-24; Watford, W. T. & O'Shea, J. J., 2006, Immunity25:695-697). Consistent with this, primary cells derived from a TYK2deficient human are defective in type I interferon, IL-6, IL-10, IL-12and IL-23 signaling. A fully human monoclonal antibody targeting theshared p40 subunit of the IL-12 and IL-23 cytokines (Ustekinumab) wasrecently approved by the European Commission for the treatment ofmoderate-to-severe plaque psoriasis (Krueger et al., 2007, N. Engl. J.Med. 356:580-92; Reich et al., 2009, Nat. Rev. Drug Discov. 8:355-356).In addition, an antibody targeting the IL-12 and IL-23 pathwaysunderwent clinical trials for treating Crohn's Disease (Mannon et al.,2004, N. Engl. J. Med. 351:2069-79).

International Patent Application Publication Numbers WO 2010/051549, WO2011/003065, WO 2015/177326 and WO 2017/089390 discuss certainpyrazolopyrimidine compounds that are reported to useful as inhibitorsof one or more Janus kinases. Data for certain specific compoundsshowing inhibition of JAK1 as well as JAK2, JAK3, and/or TYK2 kinases ispresented therein.

Currently there remains a need for additional compounds that areinhibitors of Janus kinases. For example, there is a need for compoundsthat possess useful potency as inhibitors of one or more Janus kinases(e.g., JAK1) in combination with other pharmacological properties thatare necessary to achieve a useful therapeutic benefit. For example,there is a need for potent compounds that demonstrate selectivity forone Janus kinase over other kinases in general (e.g., selectivity forJAK1 over other kinases such as leucine-rich repeat kinase 2 (LRRK2)).There is also a need for potent compounds that demonstrate selectivityfor one Janus kinase over other Janus kinases (e.g., selectivity forJAK1 over other Janus kinases). Kinases demonstrating selectivity forJAK1 could provide a therapeutic benefit, with fewer side effects, inconditions responsive to the inhibition of JAK1. Additionally there iscurrently a need for potent JAK1 inhibitors that possess otherproperties (e.g., melting point, pK, solubility, etc.) necessary forformulation and administration by inhalation. Such compounds would beparticularly useful for treating conditions such as, for example,asthma.

There exists a need in the art for additional or alternative treatmentsof conditions mediated by JAK kinases, such as those described above.

SUMMARY OF THE INVENTION

Provided herein are pyrazolopyrimidines that inhibit JAK kinase, such asselected from a compound of Formula (I) a stereoisomer or salt thereof,such as a pharmaceutically acceptable salt thereof. The JAK kinase maybe JAK1.

One embodiment provides a compound of Formula (I):

or a stereoisomer or salt (e.g., a pharmaceutically acceptable salt)thereof, wherein:

R¹ is hydrogen or CH₃;

R² is halogen, C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₃-C₆cycloalkyl,or —OR^(a), wherein R² is optionally substituted by one or more groupsindependently selected from the group consisting of halogen, C₁-C₃alkyl,cyano, hydroxy and oxo;

R^(a) is C₁-C₆alkyl, -phenyl-COR^(b)R^(c), -phenyl-(3-6-memberedheterocyclyl), or 3-11-membered heterocyclyl, wherein R^(a) isoptionally substituted by one or more groups independently selected fromthe group consisting of halogen, C₁-C₃alkyl, cyano, hydroxy and oxo;

R^(b) and R^(c) are each independently hydrogen or CH₃;

R³ is hydrogen or NH₂;

R⁴ is hydrogen or CH₃; and

R⁵ is hydrogen or NH₂.

Also provided is a pharmaceutical composition comprising a JAK inhibitoras described herein, or a pharmaceutically acceptable salt thereof, anda pharmaceutically acceptable carrier, dilient or excipient.

Also provided is the use of a JAK inhibitor as described herein, or apharmaceutically acceptable salt thereof in therapy, such as in thetreatment of an inflammatory disease (e.g., asthma). Also provided isthe use of a JAK inhibitor as described herein or a pharmaceuticallyacceptable salt thereof for the preparation of a medicament for thetreatment of an inflammatory disease. Also provided is a method ofpreventing, treating or lessening the severity of a disease or conditionresponsive to the inhibition of a Janus kinase activity in a patient,comprising administering to the patient a therapeutically effectiveamount of a JAK inhibitor as described herein or a pharmaceuticallyacceptable salt thereof.

Certain compounds or salts thereof (e.g., pharmaceutically acceptablesalts thereof) described herein possess beneficial potency as inhibitorsof one or more Janus kinases (e.g., JAK1). Certain compounds or saltsthereof (e.g., pharmaceutically acceptable salts thereof) are also a)selective for one Janus kinase over other kinases, b) selective for JAK1over other Janus kinases, and/or c) possess other properties (e.g.,melting point, pK, solubility, etc.) necessary for formulation andadministration by inhalation. Certain compounds or salts thereof (e.g.,pharmaceutically acceptable salts thereof) described herein may beparticularly useful for treating conditions such as asthma.

DETAILED DESCRIPTION OF THE INVENTION Definitions

“Halogen” or “halo” refers to F, Cl, Br or I. Additionally, terms suchas “haloalkyl,” are meant to include monohaloalkyl and polyhaloalkyl,wherein one or more halogens replace a hydrogen(s) of an alkyl group.

The term “alkyl” refers to a saturated linear or branched-chainmonovalent hydrocarbon radical, wherein the alkyl radical may beoptionally substituted. In one example, the alkyl radical is one toeighteen carbon atoms (C₁-C₁₈). In other examples, the alkyl radical isC₀-C₆, C₀-C₅, C₀-C₃, C₁-C₁₂, C₁-C₁₀, C₁-C₈, C₁-C₆, C₁-C₅, C₁-C₄, orC₁-C₃. C₀ alkyl refers to a bond. Examples of alkyl groups includemethyl (Me, —CH₃), ethyl (Et, —CH₂CH₃), 1-propyl (n-Pr, n-propyl,—CH₂CH₂CH₃), 2-propyl (i-Pr, i-propyl, —CH(CH₃)₂), 1-butyl (n-Bu,n-butyl, —CH₂CH₂CH₂CH₃), 2-methyl-1-propyl (i-Bu, i-butyl,—CH₂CH(CH₃)₂), 2-butyl (s-Bu, s-butyl, —CH(CH₃)CH₂CH₃),2-methyl-2-propyl (t-Bu, t-butyl, —C(CH₃)₃), 1-pentyl (n-pentyl,—CH₂CH₂CH₂CH₂CH₃), 2-pentyl (—CH(CH₃)CH₂CH₂CH₃), 3-pentyl(—CH(CH₂CH₃)₂), 2-methyl-2-butyl (—C(CH₃)₂CH₂CH₃), 3-methyl-2-butyl(—CH(CH₃)CH(CH₃)₂), 3-methyl-1-butyl (—CH₂CH₂CH(CH₃)₂), 2-methyl-1-butyl(—CH₂CH(CH₃)CH₂CH₃), 1-hexyl (—CH₂CH₂CH₂CH₂CH₂CH₃), 2-hexyl(—CH(CH₃)CH₂CH₂CH₂CH₃), 3-hexyl (—CH(CH₂CH₃)(CH₂CH₂CH₃)),2-methyl-2-pentyl (—C(CH₃)₂CH₂CH₂CH₃), 3-methyl-2-pentyl(—CH(CH₃)CH(CH₃)CH₂CH₃), 4-methyl-2-pentyl (—CH(CH₃)CH₂CH(CH₃)₂),3-methyl-3-pentyl (—C(CH₃)(CH₂CH₃)₂), 2-methyl-3-pentyl(—CH(CH₂CH₃)CH(CH₃)₂), 2,3-dimethyl-2-butyl (—C(CH₃)₂CH(CH₃)₂),3,3-dimethyl-2-butyl (—CH(CH₃)C(CH₃)₃, 1-heptyl and 1-octyl. In someembodiments, substituents for “optionally substituted alkyls” includeone to four instances of F, Cl, Br, I, OH, SH, CN, NH₂, NHCH₃, N(CH₃)₂,NO₂, N₃, C(O)CH₃, COOH, CO₂CH₃, methyl, ethyl, propyl, iso-propyl,butyl, isobutyl, cyclopropyl, methoxy, ethoxy, propoxy, oxo,trifluoromethyl, difluoromethyl, sulfonylamino, methanesulfonylamino,SO, SO₂, phenyl, piperidinyl, piperizinyl, and pyrimidinyl, wherein thealkyl, phenyl and heterocyclic portions thereof may be optionallysubstituted, such as by one to four instances of substituents selectedfrom this same list.

The term “alkenyl” refers to linear or branched-chain monovalenthydrocarbon radical with at least one site of unsaturation, i.e., acarbon-carbon double bond, wherein the alkenyl radical may be optionallysubstituted, and includes radicals having “cis” and “trans”orientations, or alternatively, “E” and “Z” orientations. In oneexample, the alkenyl radical is two to eighteen carbon atoms (C₂-C₁₈).In other examples, the alkenyl radical is C₂-C₁₂, C₂-C₁₀, C₂-C₈, C₂-C₆or C₂-C₃. Examples include, but are not limited to, ethenyl or vinyl(—CH═CH₂), prop-1-enyl (—CH═CHCH₃), prop-2-enyl (—CH₂CH═CH₂),2-methylprop-1-enyl, but-1-enyl, but-2-enyl, but-3-enyl,buta-1,3-dienyl, 2-methylbuta-1,3-diene, hex-1-enyl, hex-2-enyl,hex-3-enyl, hex-4-enyl and hexa-1,3-dienyl. In some embodiments,substituents for “optionally substituted alkenyls” include one to fourinstances of F, Cl, Br, I, OH, SH, CN, NH₂, NHCH₃, N(CH₃)₂, NO₂, N₃,C(O)CH₃, COOH, CO₂CH₃, methyl, ethyl, propyl, iso-propyl, butyl,isobutyl, cyclopropyl, methoxy, ethoxy, propoxy, oxo, trifluoromethyl,difluoromethyl, sulfonylamino, methanesulfonylamino, SO, SO₂, phenyl,piperidinyl, piperizinyl, and pyrimidinyl, wherein the alkyl, phenyl andheterocyclic portions thereof may be optionally substituted, such as byone to four instances of substituents selected from this same list.

The term “alkynyl” refers to a linear or branched monovalent hydrocarbonradical with at least one site of unsaturation, i.e., a carbon-carbon,triple bond, wherein the alkynyl radical may be optionally substituted.In one example, the alkynyl radical is two to eighteen carbon atoms(C₂-C₁₈). In other examples, the alkynyl radical is C₂-C₁₂, C₂-C₁₀,C₂-C₈, C₂-C₆ or C₂-C₃. Examples include, but are not limited to, ethynyl(—C≡CH), prop-1-ynyl (—C≡CCH₃), prop-2-ynyl (propargyl, —CH₂C≡CH),but-1-ynyl, but-2-ynyl and but-3-ynyl. In some embodiments, substituentsfor “optionally substituted alkynyls” include one to four instances ofF, Cl, Br, I, OH, SH, CN, NH₂, NHCH₃, N(CH₃)₂, NO₂, N₃, C(O)CH₃, COOH,CO₂CH₃, methyl, ethyl, propyl, iso-propyl, butyl, isobutyl, cyclopropyl,methoxy, ethoxy, propoxy, oxo, trifluoromethyl, difluoromethyl,sulfonylamino, methanesulfonylamino, SO, SO₂, phenyl, piperidinyl,piperizinyl, and pyrimidinyl, wherein the alkyl, phenyl and heterocyclicportions thereof may be optionally substituted, such as by one to fourinstances of substituents selected from this same list.

“Alkylene” refers to a saturated, branched or straight chain hydrocarbongroup having two monovalent radical centers derived by the removal oftwo hydrogen atoms from the same or two different carbon atoms of aparent alkane. In one example, the divalent alkylene group is one toeighteen carbon atoms (C₁-C₁₈). In other examples, the divalent alkylenegroup is C₀-C₆, C₀-C₅, C₀-C₃, C₁-C₁₀, C₁-C₈, C₁-C₆, C₁-C₅, C₁-C₄, orC₁-C₃. The group C₀ alkylene refers to a bond. Example alkylene groupsinclude methylene (—CH₂—), 1,1-ethyl (—CH(CH₃)—), (1,2-ethyl (—CH₂CH₂—),1,1-propyl (—CH(CH₂CH₃)—), 2,2-propyl (—C(CH₃)₂—), 1,2-propyl(—CH(CH₃)CH₂—), 1,3-propyl (—CH₂CH₂CH₂—), 1,1-dimethyleth-1,2-yl(—C(CH₃)₂CH₂—), 1,4-butyl (—CH₂CH₂CH₂CH₂—), and the like.

The term “heteroalkyl” refers to a straight or branched chain monovalenthydrocarbon radical, consisting of the stated number of carbon atoms,or, if none are stated, up to 18 carbon atoms, and from one to fiveheteroatoms selected from the group consisting of O, N, Si and S, andwherein the nitrogen and sulfur atoms can optionally be oxidized and thenitrogen heteroatom can optionally be quaternized. In some embodiments,the heteroatom is selected from O, N and S, wherein the nitrogen andsulfur atoms can optionally be oxidized and the nitrogen heteroatom canoptionally be quaternized. The heteroatom(s) can be placed at anyinterior position of the heteroalkyl group, including the position atwhich the alkyl group is attached to the remainder of the molecule(e.g., —O—CH₂—CH₃). Examples include —CH₂—CH₂—O—CH₃, —CH₂—CH₂—NH—CH₃,—CH₂—CH₂—N(CH₃)—CH₃, —CH₂—S—CH₂—CH₃, —S(O)—CH₃, —CH₂—CH₂—S(O)₂—CH₃,—Si(CH₃)₃ and —CH₂—CH═N—OCH₃. Up to two heteroatoms can be consecutive,such as, for example, —CH₂—NH—OCH₃ and —CH₂—O—Si(CH₃)₃. Heteroalkylgroups can be optionally substituted. In some embodiments, substituentsfor “optionally substituted heteroalkyls” include one to four instancesof F, Cl, Br, I, OH, SH, CN, NH₂, NHCH₃, N(CH₃)₂, NO₂, N₃, C(O)CH₃,COOH, CO₂CH₃, methyl, ethyl, propyl, iso-propyl, butyl, isobutyl,cyclopropyl, methoxy, ethoxy, propoxy, oxo, trifluoromethyl,difluoromethyl, sulfonylamino, methanesulfonylamino, SO, SO₂, phenyl,piperidinyl, piperizinyl, and pyrimidinyl, wherein the alkyl, phenyl andheterocyclic portions thereof may be optionally substituted, such as byone to four instances of substituents selected from this same list.

“Amino” means primary (i.e., —NH₂), secondary (i.e., —NRH), tertiary(i.e., —NRR) and quaternary (i.e., —N(+)RRR) amines, that are optionallysubstituted, in which each R is the same or different and selected fromalkyl, cycloalkyl, aryl, and heterocyclyl, wherein the alkyl,cycloalkyl, aryl and heterocyclyl groups are as defined herein.Particular secondary and tertiary amines are alkylamine, dialkylamine,arylamine, diarylamine, aralkylamine and diaralkylamine, wherein thealkyl and aryl portions can be optionally substituted. Particularsecondary and tertiary amines are methylamine, ethylamine, propylamine,isopropylamine, phenylamine, benzylamine, dimethylamine, diethylamine,dipropylamine and diisopropylamine. In some embodiments, R groups of aquarternary amine are each independently optionally substituted alkylgroups.

“Aryl” refers to a carbocyclic aromatic group, whether or not fused toone or more groups, having the number of carbon atoms designated, or ifno number is designated, up to 14 carbon atoms. One example includesaryl groups having 6-14 carbon atoms. Another example includes arylgroups having 6-10 carbon atoms. Examples of aryl groups include phenyl,naphthyl, biphenyl, phenanthrenyl, naphthacenyl,1,2,3,4-tetrahydronaphthalenyl, 1H-indenyl, 2,3-dihydro-1H-indenyl, andthe like (see, e.g., Lang's Handbook of Chemistry (Dean, J. A., ed.)13^(th) ed. Table 7-2 [1985]). A particular aryl is phenyl. Substitutedphenyl or substituted aryl means a phenyl group or aryl groupsubstituted with one, two, three, four or five substituents, forexample, 1-2, 1-3 or 1-4 substituents, such as chosen from groupsspecified herein (see “optionally substituted” definition), such as F,Cl, Br, I, OH, SH, CN, NH₂, NHCH₃, N(CH₃)₂, NO₂, N₃, C(O)CH₃, COOH,CO₂CH₃, methyl, ethyl, propyl, iso-propyl, butyl, isobutyl, cyclopropyl,methoxy, ethoxy, propoxy, oxo, trifluoromethyl, difluoromethyl,sulfonylamino, methanesulfonylamino, SO, SO₂, phenyl, piperidinyl,piperizinyl, and pyrimidinyl, wherein the alkyl, phenyl and heterocyclicportions thereof may be optionally substituted, such as by one to fourinstances of substituents selected from this same list. Examples of theterm “substituted phenyl” include a mono- or di(halo)phenyl group suchas 2-chlorophenyl, 2-bromophenyl, 4-chlorophenyl, 2,6-dichlorophenyl,2,5-dichlorophenyl, 3,4-dichlorophenyl, 3-chlorophenyl, 3-bromophenyl,4-bromophenyl, 3,4-dibromophenyl, 3-chloro-4-fluorophenyl,2-fluorophenyl, 2,4-difluorophenyl and the like; a mono- ordi(hydroxy)phenyl group such as 4-hydroxyphenyl, 3-hydroxyphenyl,2,4-dihydroxyphenyl, the protected-hydroxy derivatives thereof and thelike; a nitrophenyl group such as 3- or 4-nitrophenyl; a cyanophenylgroup, for example, 4-cyanophenyl; a mono- or di(alkyl)phenyl group suchas 4-methylphenyl, 2,4-dimethylphenyl, 2-methylphenyl,4-(isopropyl)phenyl, 4-ethylphenyl, 3-(n-propyl)phenyl and the like; amono or di(alkoxy)phenyl group, for example, 3,4-dimethoxyphenyl,3-methoxy-4-benzyloxyphenyl, 3-ethoxyphenyl, 4-(isopropoxy)phenyl,4-(t-butoxy)phenyl, 3-ethoxy-4-methoxyphenyl and the like; 3- or4-trifluoromethylphenyl; a mono- or dicarboxyphenyl or (protectedcarboxy)phenyl group such 4-carboxyphenyl, a mono- ordi(hydroxymethyl)phenyl or (protected hydroxymethyl)phenyl such as3-(protected hydroxymethyl)phenyl or 3,4-di(hydroxymethyl)phenyl; amono- or di(aminomethyl)phenyl or (protected aminomethyl)phenyl such as2-(aminomethyl)phenyl or 2,4-(protected aminomethyl)phenyl; or a mono-or di(N-(methylsulfonylamino))phenyl such as3-(N-methylsulfonylamino))phenyl. Also, the term “substituted phenyl”represents disubstituted phenyl groups where the substituents aredifferent, for example, 3-methyl-4-hydroxyphenyl,3-chloro-4-hydroxyphenyl, 2-methoxy-4-bromophenyl,4-ethyl-2-hydroxyphenyl, 3-hydroxy-4-nitrophenyl,2-hydroxy-4-chlorophenyl, 2-chloro-5-difluoromethoxy and the like, aswell as trisubstituted phenyl groups where the substituents aredifferent, for example 3-methoxy-4-benzyloxy-6-methyl sulfonylamino,3-methoxy-4-benzyloxy-6-phenyl sulfonylamino, and tetrasubstitutedphenyl groups where the substituents are different such as3-methoxy-4-benzyloxy-5-methyl-6-phenyl sulfonylamino. In someembodiments, a substituent of an aryl, such as phenyl, comprises anamide. For example, an aryl (e.g., phenyl) substituent may be—(CH₂)₀₋₄CONR′R″, wherein R′ and R″ each independently refer to groupsincluding, for example, hydrogen; unsubstituted C₁-C₆alkyl; C₁-C₆alkylsubstituted by halogen, OH, CN, unsubstituted C₁-C₆alkyl, unsubstitutedC₁-C₆ alkoxy, oxo or NR′R″; unsubstituted C₁-C₆ heteroalkyl; C₁-C₆heteroalkyl substituted by halogen, OH, CN, unsubstituted C₁-C₆alkyl,unsubstituted C₁-C₆ alkoxy, oxo or NR′R″; unsubstituted C₆-C₁₀ aryl;C₆-C₁₀ aryl substituted by halogen, OH, CN, unsubstituted C₁-C₆alkyl,unsubstituted C₁-C₆ alkoxy, or NR′R″; unsubstituted 3-11 memberedheterocyclyl (e.g., 5-6 membered heteroaryl containing 1 to 4heteroatoms selected from O, N and S or 4-11 membered heterocycloalkylcontaining 1 to 4 heteroatoms selected from 0, N and S); and 3-11membered heterocyclyl (e.g., 5-6 membered heteroaryl containing 1 to 4heteroatoms selected from O, N and S or 4-11 membered heterocycloalkylcontaining 1 to 4 heteroatoms selected from O, N and S) substituted byhalogen, OH, CN, unsubstituted C₁-C₆alkyl, unsubstituted C₁-C₆ alkoxy,oxo or NR′R″; or R′ and R″ can be combined with the nitrogen atom toform a 3-, 4-, 5-, 6-, or 7-membered ring wherein a ring atom isoptionally substituted with N, O or S and wherein the ring is optionallysubstituted with halogen, OH, CN, unsubstituted C₁-C₆alkyl,unsubstituted C₁-C₆ alkoxy, oxo or NR′R″.

“Cycloalkyl” refers to a non-aromatic, saturated or partiallyunsaturated hydrocarbon ring group wherein the cycloalkyl group may beoptionally substituted independently with one or more substituentsdescribed herein. In one example, the cycloalkyl group is 3 to 12 carbonatoms (C₃-C₁₂). In other examples, cycloalkyl is C₃-C₈, C₃-C₁₀ orC₅-C₁₀. In other examples, the cycloalkyl group, as a monocycle, isC₃-C₈, C₃-C₆ or C₅-C₆. In another example, the cycloalkyl group, as abicycle, is C₇-C₁₂. In another example, the cycloalkyl group, as a spirosystem, is C₅-C₁₂. Examples of monocyclic cycloalkyl includecyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopent-1-enyl,1-cyclopent-2-enyl, 1-cyclopent-3-enyl, cyclohexyl,perdeuteriocyclohexyl, 1-cyclohex-1-enyl, 1-cyclohex-2-enyl,1-cyclohex-3-enyl, cyclohexadienyl, cycloheptyl, cyclooctyl, cyclononyl,cyclodecyl, cycloundecyl and cyclododecyl. Exemplary arrangements ofbicyclic cycloalkyls having 7 to 12 ring atoms include, but are notlimited to, [4,4], [4,5], [5,5], [5,6] or [6,6] ring systems. Exemplarybridged bicyclic cycloalkyls include, but are not limited to,bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane and bicyclo[3.2.2]nonane.Examples of spiro cycloalkyl include, spiro[2.2]pentane,spiro[2.3]hexane, spiro[2.4]heptane, spiro[2.5]octane andspiro[4.5]decane. In some embodiments, substituents for “optionallysubstituted cycloalkyls” include one to four instances of F, Cl, Br, I,OH, SH, CN, NH₂, NHCH₃, N(CH₃)₂, NO₂, N₃, C(O)CH₃, COOH, CO₂CH₃, methyl,ethyl, propyl, iso-propyl, butyl, isobutyl, cyclopropyl, methoxy,ethoxy, propoxy, oxo, trifluoromethyl, difluoromethyl, sulfonylamino,methanesulfonylamino, SO, SO₂, phenyl, piperidinyl, piperizinyl, andpyrimidinyl, wherein the alkyl, aryl and heterocyclic portions thereofmay be optionally substituted, such as by one to four instances ofsubstituents selected from this same list. In some embodiments, asubstituent of a cycloalkyl comprises an amide. For example, acycloalkyl substituent may be —(CH₂)₀₋₄CONR′R″, wherein R′ and R″ eachindependently refer to groups including, for example, hydrogen;unsubstituted C₁-C₆alkyl; C₁-C₆alkyl substituted by halogen, OH, CN,unsubstituted C₁-C₆alkyl, unsubstituted C₁-C₆ alkoxy, oxo or NR′R″;unsubstituted C₁-C₆ heteroalkyl; C₁-C₆ heteroalkyl substituted byhalogen, OH, CN, unsubstituted C₁-C₆alkyl, unsubstituted C₁-C₆ alkoxy,oxo or NR′R″; unsubstituted C₆-C₁₀ aryl; C₆-C₁₀ aryl substituted byhalogen, OH, CN, unsubstituted C₁-C₆alkyl, unsubstituted C₁-C₆ alkoxy,or NR′R″; unsubstituted 3-11 membered heterocyclyl (e.g., 5-6 memberedheteroaryl containing 1 to 4 heteroatoms selected from O, N and S or4-11 membered heterocycloalkyl containing 1 to 4 heteroatoms selectedfrom O, N and S); and 3-11 membered heterocyclyl (e.g., 5-6 memberedheteroaryl containing 1 to 4 heteroatoms selected from O, N and S or4-11 membered heterocycloalkyl containing 1 to 4 heteroatoms selectedfrom O, N and S) substituted by halogen, OH, CN, unsubstitutedC₁-C₆alkyl, unsubstituted C₁-C₆ alkoxy, oxo or NR′R″; or R′ and R″ canbe combined with the nitrogen atom to form a 3-, 4-, 5-, 6-, or7-membered ring wherein a ring atom is optionally substituted with N, Oor S and wherein the ring is optionally substituted with halogen, OH,CN, unsubstituted C₁-C₆alkyl, unsubstituted C₁-C₆ alkoxy, oxo or NR′R″.

“Heterocyclic group”, “heterocyclic”, “heterocycle”, “heterocyclyl”, or“heterocyclo” are used interchangeably and refer to any mono-, bi-,tricyclic or spiro, saturated or unsaturated, aromatic (heteroaryl) ornon-aromatic (e.g., heterocycloalkyl), ring system, having 3 to 20 ringatoms (e.g., 3-10 ring atoms), where the ring atoms are carbon, and atleast one atom in the ring or ring system is a heteroatom selected fromnitrogen, sulfur or oxygen. If any ring atom of a cyclic system is aheteroatom, that system is a heterocycle, regardless of the point ofattachment of the cyclic system to the rest of the molecule. In oneexample, heterocyclyl includes 3-11 ring atoms (“members”) and includesmonocycles, bicycles, tricycles and spiro ring systems, wherein the ringatoms are carbon, where at least one atom in the ring or ring system isa heteroatom selected from nitrogen, sulfur or oxygen. In one example,heterocyclyl includes 1 to 4 heteroatoms. In one example, heterocyclylincludes 1 to 3 heteroatoms. In another example, heterocyclyl includes3- to 7-membered monocycles having 1-2, 1-3 or 1-4 heteroatoms selectedfrom nitrogen, sulfur or oxygen. In another example, heterocyclylincludes 4- to 6-membered monocycles having 1-2, 1-3 or 1-4 heteroatomsselected from nitrogen, sulfur or oxygen. In another example,heterocyclyl includes 3-membered monocycles. In another example,heterocyclyl includes 4-membered monocycles. In another example,heterocyclyl includes 5-6 membered monocycles, e.g., 5-6 memberedheteroaryl. In another example, heterocyclyl includes 3-11 memberedheterocycloyalkyls, such as 4-11 membered heterocycloalkyls. In someembodiments, a heterocycloalkyl includes at least one nitrogen. In oneexample, the heterocyclyl group includes 0 to 3 double bonds. Anynitrogen or sulfur heteroatom may optionally be oxidized (e.g., NO, SO,SO₂), and any nitrogen heteroatom may optionally be quaternized (e.g.,[NR₄]⁺Cl⁻, [NR₄]⁺OH⁻). Example heterocycles are oxiranyl, aziridinyl,thiiranyl, azetidinyl, oxetanyl, thietanyl, 1,2-dithietanyl,1,3-dithietanyl, pyrrolidinyl, dihydro-1H-pyrrolyl, dihydrofuranyl,tetrahydrofuranyl, dihydrothienyl, tetrahydrothienyl, imidazolidinyl,piperidinyl, piperazinyl, isoquinolinyl, tetrahydroisoquinolinyl,morpholinyl, thiomorpholinyl, 1,1-dioxo-thiomorpholinyl, dihydropyranyl,tetrahydropyranyl, hexahydrothiopyranyl, hexahydropyrimidinyl,oxazinanyl, thiazinanyl, thioxanyl, homopiperazinyl, homopiperidinyl,azepanyl, oxepanyl, thiepanyl, oxazepinyl, oxazepanyl, diazepanyl,1,4-diazepanyl, diazepinyl, thiazepinyl, thiazepanyl,tetrahydrothiopyranyl, oxazolidinyl, thiazolidinyl, isothiazolidinyl,1,1-dioxoisothiazolidinonyl, oxazolidinonyl, imidazolidinonyl,4,5,6,7-tetrahydro[2H]indazolyl, tetrahydrobenzoimidazolyl,4,5,6,7-tetrahydrobenzo[d]imidazolyl,1,6-dihydroimidazol[4,5-d]pyrrolo[2,3-b]pyridinyl, thiazinyl, oxazinyl,thiadiazinyl, oxadiazinyl, dithiazinyl, dioxazinyl, oxathiazinyl,thiatriazinyl, oxatriazinyl, dithiadiazinyl, imidazolinyl,dihydropyrimidyl, tetrahydropyrimidyl, 1-pyrrolinyl, 2-pyrrolinyl,3-pyrrolinyl, indolinyl, thiapyranyl, 2H-pyranyl, 4H-pyranyl, dioxanyl,1,3-dioxolanyl, pyrazolinyl, pyrazolidinyl, dithianyl, dithiolanyl,pyrimidinonyl, pyrimidindionyl, pyrimidin-2,4-dionyl, piperazinonyl,piperazindionyl, pyrazolidinylimidazolinyl, 3-azabicyclo[3.1.0]hexanyl,3,6-diazabicyclo[3.1.1]heptanyl, 6-azabicyclo[3.1.1]heptanyl,3-azabicyclo[3.1.1]heptanyl, 3-azabicyclo[4.1.0]heptanyl,azabicyclo[2.2.2]hexanyl, 2-azabicyclo[3.2.1]octanyl,8-azabicyclo[3.2.1]octanyl, 2-azabicyclo[2.2.2]octanyl,8-azabicyclo[2.2.2]octanyl, 7-oxabicyclo[2.2.1]heptane,azaspiro[3.5]nonanyl, azaspiro[2.5]octanyl, azaspiro[4.5]decanyl,1-azaspiro[4.5]decan-2-only, azaspiro[5.5]undecanyl, tetrahydroindolyl,octahydroindolyl, tetrahydroisoindolyl, tetrahydroindazolyl,1,1-dioxohexahydrothiopyranyl. Examples of 5-membered heterocyclescontaining a sulfur or oxygen atom and one to three nitrogen atoms arethiazolyl, including thiazol-2-yl and thiazol-2-yl N-oxide,thiadiazolyl, including 1,3,4-thiadiazol-5-yl and 1,2,4-thiadiazol-5-yl,oxazolyl, for example oxazol-2-yl, and oxadiazolyl, such as1,3,4-oxadiazol-5-yl, and 1,2,4-oxadiazol-5-yl. Example 5-membered ringheterocycles containing 2 to 4 nitrogen atoms include imidazolyl, suchas imidazol-2-yl; triazolyl, such as 1,3,4-triazol-5-yl;1,2,3-triazol-5-yl, 1,2,4-triazol-5-yl, and tetrazolyl, such as1H-tetrazol-5-yl. Example benzo-fused 5-membered heterocycles arebenzoxazol-2-yl, benzthiazol-2-yl and benzimidazol-2-yl. Example6-membered heterocycles contain one to three nitrogen atoms andoptionally a sulfur or oxygen atom, for example pyridyl, such aspyrid-2-yl, pyrid-3-yl, and pyrid-4-yl; pyrimidyl, such as pyrimid-2-yland pyrimid-4-yl; triazinyl, such as 1,3,4-triazin-2-yl and1,3,5-triazin-4-yl; pyridazinyl, in particular pyridazin-3-yl, andpyrazinyl. The pyridine N-oxides and pyridazine N-oxides and thepyridyl, pyrimid-2-yl, pyrimid-4-yl, pyridazinyl and the1,3,4-triazin-2-yl groups, are other example heterocycle groups.Heterocycles may be optionally substituted. For example, substituentsfor “optionally substituted heterocycles” include one to four instancesof F, Cl, Br, I, OH, SH, CN, NH₂, NHCH₃, N(CH₃)₂, NO₂, N₃, C(O)CH₃,COOH, CO₂CH₃, methyl, ethyl, propyl, iso-propyl, butyl, isobutyl,cyclopropyl, methoxy, ethoxy, propoxy, oxo, trifluoromethyl,difluoromethyl, sulfonylamino, methanesulfonylamino, SO, SO₂, phenyl,piperidinyl, piperizinyl, and pyrimidinyl, wherein the alkyl, aryl andheterocyclic portions thereof may be optionally substituted, such as byone to four instances of substituents selected from this same list. Insome embodiments, a substituent of a heterocyclic group, such as aheteroaryl or heterocycloalkyl, comprises an amide. For example, aheterocyclic (e.g., heteroaryl or heterocycloalkyl) substituent may be—(CH₂)₀₋₄CONR′R″, wherein R′ and R″ each independently refer to groupsincluding, for example, hydrogen; unsubstituted C₁-C₆alkyl; C₁-C₆alkylsubstituted by halogen, OH, CN, unsubstituted C₁-C₆alkyl, unsubstitutedC₁-C₆ alkoxy, oxo or NR′R″; unsubstituted C₁-C₆ heteroalkyl; C₁-C₆heteroalkyl substituted by halogen, OH, CN, unsubstituted C₁-C₆alkyl,unsubstituted C₁-C₆ alkoxy, oxo or NR′R″; unsubstituted C₆-C₁₀ aryl;C₆-C₁₀ aryl substituted by halogen, OH, CN, unsubstituted C₁-C₆alkyl,unsubstituted C₁-C₆ alkoxy, or NR′R″; unsubstituted 3-11 memberedheterocyclyl (e.g., 5-6 membered heteroaryl containing 1 to 4heteroatoms selected from O, N and S or 4-11 membered heterocycloalkylcontaining 1 to 4 heteroatoms selected from O, N and S); and 3-11membered heterocyclyl (e.g., 5-6 membered heteroaryl containing 1 to 4heteroatoms selected from O, N and S or 4-11 membered heterocycloalkylcontaining 1 to 4 heteroatoms selected from O, N and S) substituted byhalogen, OH, CN, unsubstituted C₁-C₆alkyl, unsubstituted C₁-C₆ alkoxy,oxo or NR′R″; or R′ and R″ can be combined with the nitrogen atom toform a 3-, 4-, 5-, 6-, or 7-membered ring wherein a ring atom isoptionally substituted with N, O or S and wherein the ring is optionallysubstituted with halogen, OH, CN, unsubstituted C₁-C₆alkyl,unsubstituted C₁-C₆ alkoxy, oxo or NR′R″.

“Heteroaryl” refers to any mono-, bi-, or tricyclic ring system where atleast one ring is a 5- or 6-membered aromatic ring containing from 1 to4 heteroatoms selected from nitrogen, oxygen, and sulfur, and in anexample embodiment, at least one heteroatom is nitrogen. See, forexample, Lang's Handbook of Chemistry (Dean, J. A., ed.) 13^(th) ed.Table 7-2 [1985]. Included in the definition are any bicyclic groupswhere any of the above heteroaryl rings are fused to an aryl ring,wherein the aryl ring or the heteroaryl ring is joined to the remainderof the molecule. In one embodiment, heteroaryl includes 5-6 memberedmonocyclic aromatic groups where one or more ring atoms is nitrogen,sulfur or oxygen. Example heteroaryl groups include thienyl, furyl,imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl,triazolyl, thiadiazolyl, oxadiazolyl, tetrazolyl, thiatriazolyl,oxatriazolyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, triazinyl,tetrazinyl, tetrazolo[1,5-b]pyridazinyl, imidazol[1,2-a]pyrimidinyl andpurinyl, as well as benzo-fused derivatives, for example benzoxazolyl,benzofuryl, benzothiazolyl, benzothiadiazolyl, benzotriazolyl,benzoimidazolyl and indolyl. Heteroaryl groups can be optionallysubstituted. In some embodiments, substituents for “optionallysubstituted heteroaryls” include one to four instances of F, Cl, Br, I,OH, SH, CN, NH₂, NHCH₃, N(CH₃)₂, NO₂, N₃, C(O)CH₃, COOH, CO₂CH₃, methyl,ethyl, propyl, iso-propyl, butyl, isobutyl, cyclopropyl, methoxy,ethoxy, propoxy, trifluoromethyl, difluoromethyl, sulfonylamino,methanesulfonylamino, SO, SO₂, phenyl, piperidinyl, piperizinyl, andpyrimidinyl, wherein the alkyl, phenyl and heterocyclic portions thereofmay be optionally substituted, such as by one to four instances ofsubstituents selected from this same list. In some embodiments, asubstituent of a heteroaryl comprises an amide. For example, aheteroaryl substituent may be —(CH₂)₀₋₄CONR′R″, wherein R′ and R″ eachindependently refer to groups including, for example, hydrogen;unsubstituted C₁-C₆alkyl; C₁-C₆alkyl substituted by halogen, OH, CN,unsubstituted C₁-C₆alkyl, unsubstituted C₁-C₆ alkoxy, oxo or NR′R″;unsubstituted C₁-C₆ heteroalkyl; C₁-C₆ heteroalkyl substituted byhalogen, OH, CN, unsubstituted C₁-C₆alkyl, unsubstituted C₁-C₆ alkoxy,oxo or NR′R″; unsubstituted C₆-C₁₀ aryl; C₆-C₁₀ aryl substituted byhalogen, OH, CN, unsubstituted C₁-C₆alkyl, unsubstituted C₁-C₆ alkoxy,or NR′R″; unsubstituted 3-11 membered heterocyclyl (e.g., 5-6 memberedheteroaryl containing 1 to 4 heteroatoms selected from O, N and S or4-11 membered heterocycloalkyl containing 1 to 4 heteroatoms selectedfrom O, N and S); and 3-11 membered heterocyclyl (e.g., 5-6 memberedheteroaryl containing 1 to 4 heteroatoms selected from O, N and S or4-11 membered heterocycloalkyl containing 1 to 4 heteroatoms selectedfrom O, N and S) substituted by halogen, OH, CN, unsubstitutedC₁-C₆alkyl, unsubstituted C₁-C₆ alkoxy, oxo or NR′R″; or R′ and R″ canbe combined with the nitrogen atom to form a 3-, 4-, 5-, 6-, or7-membered ring wherein a ring atom is optionally substituted with N, Oor S and wherein the ring is optionally substituted with halogen, OH,CN, unsubstituted C₁-C₆alkyl, unsubstituted C₁-C₆ alkoxy, oxo or NR′R″.

In particular embodiments, a heterocyclyl group is attached at a carbonatom of the heterocyclyl group. By way of example, carbon bondedheterocyclyl groups include bonding arrangements at position 2, 3, 4, 5,or 6 of a pyridine ring, position 3, 4, 5, or 6 of a pyridazine ring,position 2, 4, 5, or 6 of a pyrimidine ring, position 2, 3, 5, or 6 of apyrazine ring, position 2, 3, 4, or 5 of a furan, tetrahydrofuran,thiofuran, thiophene, pyrrole or tetrahydropyrrole ring, position 2, 4,or 5 of an oxazole, imidazole or thiazole ring, position 3, 4, or 5 ofan isoxazole, pyrazole, or isothiazole ring, position 2 or 3 of anaziridine ring, position 2, 3, or 4 of an azetidine ring, position 2, 3,4, 5, 6, 7, or 8 of a quinoline ring or position 1, 3, 4, 5, 6, 7, or 8of an isoquinoline ring.

In certain embodiments, the heterocyclyl group is N-attached. By way ofexample, nitrogen bonded heterocyclyl or heteroaryl groups includebonding arrangements at position 1 of an aziridine, azetidine, pyrrole,pyrrolidine, 2-pyrroline, 3-pyrroline, imidazole, imidazolidine,2-imidazoline, 3-imidazoline, pyrazole, pyrazoline, 2-pyrazoline,3-pyrazoline, piperidine, piperazine, indole, indoline, 1H-indazole,position 2 of a isoindole, or isoindoline, position 4 of a morpholine,and position 9 of a carbazole, or β-carboline.

The term “alkoxy” refers to a linear or branched monovalent radicalrepresented by the formula —OR in which R is alkyl, as defined herein.Alkoxy groups include methoxy, ethoxy, propoxy, isopropoxy, mono-, di-and tri-fluoromethoxy and cyclopropoxy.

“Acyl” means a carbonyl containing substituent represented by theformula —C(O)—R in which R is hydrogen, alkyl, cycloalkyl, aryl orheterocyclyl, wherein the alkyl, cycloalkyl, aryl and heterocyclyl areas defined herein. Acyl groups include alkanoyl (e.g., acetyl), aroyl(e.g., benzoyl), and heteroaroyl (e.g., pyridinoyl).

“Optionally substituted” unless otherwise specified means that a groupmay be unsubstituted or substituted by one or more (e.g., 0, 1, 2, 3, 4,or 5 or more, or any range derivable therein) of the substituents listedfor that group in which said substituents may be the same or different.In an embodiment, an optionally substituted group has 1 substituent. Inanother embodiment an optionally substituted group has 2 substituents.In another embodiment an optionally substituted group has 3substituents. In another embodiment an optionally substituted group has4 substituents. In another embodiment an optionally substituted grouphas 5 substituents.

Optional substituents for alkyl radicals, alone or as part of anothersubstituent (e.g., alkoxy), as well as alkylenyl, alkenyl, alkynyl,heteroalkyl, heterocycloalkyl, and cycloalkyl, also each alone or aspart of another substituent, can be a variety of groups, such as thosedescribed herein, as well as selected from the group consisting ofhalogen; oxo; CN; NO; N₃; —OR′; perfluoro-C₁-C₄ alkoxy; unsubstitutedC₃-C₇ cycloalkyl; C₃-C₇ cycloalkyl substituted by halogen, OH, CN,unsubstituted C₁-C₆alkyl, unsubstituted C₁-C₆ alkoxy, oxo or NR′R″;unsubstituted C₆-C₁₀ aryl (e.g., phenyl); C₆-C₁₀ aryl substituted byhalogen, OH, CN, unsubstituted C₁-C₆alkyl, unsubstituted C₁-C₆ alkoxy,or NR′R″; unsubstituted 3-11 membered heterocyclyl (e.g., 5-6 memberedheteroaryl containing 1 to 4 heteroatoms selected from O, N and S or4-11 membered heterocycloalkyl containing 1 to 4 heteroatoms selectedfrom 0, N and S); 3-11 membered heterocyclyl (e.g., 5-6 memberedheteroaryl containing 1 to 4 heteroatoms selected from O, N and S or4-11 membered heterocycloalkyl containing 1 to 4 heteroatoms selectedfrom O, N and S) substituted by halogen, OH, CN, unsubstitutedC₁-C₆alkyl, unsubstituted C₁-C₆ alkoxy, oxo or NR′R″; —NR′R″; —SR′;—SiR′R″R″′; —OC(O)R′; —C(O)R′; —CO₂R′; —CONR′R″; —OC(O)NR′R″;—NR″C(O)R′; —NR′″C(O)NR′R″; —NR″C(O)₂R′; —S(O)₂R′; —S(O)₂NR′R″;—NR′S(O)₂R″; —NR′″S(O)₂NR′R″; amidinyl; guanidinyl; —(CH₂)₁₋₄—OR′;—(CH₂)₁₋₄—NR′R″; —(CH₂)₁₋₄—SR′; —(CH₂)₁₋₄—SiR′R″R′″; —(CH₂)₁₋₄—OC(O)R′;—(CH₂)₁₋₄—C(O)R′; —(CH₂)₁₋₄—CO₂R′; and —(CH₂)₁₋₄CONR′R″, or combinationsthereof, in a number ranging from zero to (2m′+1), where m′ is the totalnumber of carbon atoms in such radical. R′, R″ and R′″ eachindependently refer to groups including, for example, hydrogen;unsubstituted C₁-C₆alkyl; C₁-C₆alkyl substituted by halogen, OH, CN,unsubstituted C₁-C₆alkyl, unsubstituted C₁-C₆ alkoxy, oxo or NR′R″;unsubstituted C₁-C₆ heteroalkyl; C₁-C₆ heteroalkyl substituted byhalogen, OH, CN, unsubstituted C₁-C₆alkyl, unsubstituted C₁-C₆ alkoxy,oxo or NR′R″; unsubstituted C₆-C₁₀ aryl; C₆-C₁₀ aryl substituted byhalogen, OH, CN, unsubstituted C₁-C₆alkyl, unsubstituted C₁-C₆ alkoxy,or NR′R″; unsubstituted 3-11 membered heterocyclyl (e.g., 5-6 memberedheteroaryl containing 1 to 4 heteroatoms selected from O, N and S or4-11 membered heterocycloalkyl containing 1 to 4 heteroatoms selectedfrom O, N and S); and 3-11 membered heterocyclyl (e.g., 5-6 memberedheteroaryl containing 1 to 4 heteroatoms selected from O, N and S or4-11 membered heterocycloalkyl containing 1 to 4 heteroatoms selectedfrom O, N and S) substituted by halogen, OH, CN, unsubstitutedC₁-C₆alkyl, unsubstituted C₁-C₆ alkoxy, oxo or NR′R″. When R′ and R″ areattached to the same nitrogen atom, they can be combined with thenitrogen atom to form a 3-, 4-, 5-, 6-, or 7-membered ring wherein aring atom is optionally substituted with N, O or S and wherein the ringis optionally substituted with halogen, OH, CN, unsubstitutedC₁-C₆alkyl, unsubstituted C₁-C₆ alkoxy, oxo or NR′R″. For example,—NR′R″ is meant to include 1-pyrrolidinyl and 4-morpholinyl.

Similarly, optional substituents for the aryl and heteroaryl groups arevaried. In some embodiments, substituents for aryl and heteroaryl groupsare selected from the group consisting of halogen; CN; NO; N₃; —OR′;perfluoro-C₁-C₄ alkoxy; unsubstituted C₃-C₇ cycloalkyl; C₃-C₇ cycloalkylsubstituted by halogen, OH, CN, unsubstituted C₁-C₆alkyl, unsubstitutedC₁-C₆ alkoxy, oxo or NR′R″; unsubstituted C₆-C₁₀ aryl (e.g., phenyl);C₆-C₁₀ aryl substituted by halogen, OH, CN, unsubstituted C₁-C₆alkyl,unsubstituted C₁-C₆ alkoxy, or NR′R″; unsubstituted 3-11 memberedheterocyclyl (e.g., 5-6 membered heteroaryl containing 1 to 4heteroatoms selected from O, N and S or 4-11 membered heterocycloalkylcontaining 1 to 4 heteroatoms selected from O, N and S); 3-11 memberedheterocyclyl (e.g., 5-6 membered heteroaryl containing 1 to 4heteroatoms selected from O, N and S or 4-11 membered heterocycloalkylcontaining 1 to 4 heteroatoms selected from O, N and S) substituted byhalogen, OH, CN, unsubstituted C₁-C₆alkyl, unsubstituted C₁-C₆ alkoxy,oxo or NR′R″; —NR′R″; —SR′; —SiR′R″R″; —OC(O)R′; —C(O)R′; —CO₂R′;—CONR′R″; —OC(O)NR′R″; —NR″C(O)R′; —NR′″C(O)NR′R″; —NR″C(O)₂R′;—S(O)₂R′; —S(O)₂NR′R″; —NR′S(O)₂R″; —NR′″S(O)₂NR′R″; amidinyl;guanidinyl; —(CH₂)₁₋₄—OR′; —(CH₂)₁₋₄—NR′R″; —(CH₂)₁₋₄—SR′;—(CH₂)₁₋₄—SiR′R″R′″; —(CH₂)₁₋₄—OC(O)R′; —(CH₂)₁₋₄—C(O)R′;—(CH₂)₁₋₄—CO₂R′; and —(CH₂)₁₋₄CONR′R″, or combinations thereof, in anumber ranging from zero to (2m′+1), where m′ is the total number ofcarbon atoms in such radical. R′, R″ and R′″ each independently refer togroups including, for example, hydrogen; unsubstituted C₁-C₆alkyl;C₁-C₆alkyl substituted by halogen, OH, CN, unsubstituted C₁-C₆alkyl,unsubstituted C₁-C₆ alkoxy, oxo or NR′R″; unsubstituted C₁-C₆heteroalkyl; C₁-C₆ heteroalkyl substituted by halogen, OH, CN,unsubstituted C₁-C₆alkyl, unsubstituted C₁-C₆ alkoxy, oxo or NR′R″;unsubstituted C₆-C₁₀ aryl; C₆-C₁₀ aryl substituted by halogen, OH, CN,unsubstituted C₁-C₆alkyl, unsubstituted C₁-C₆ alkoxy, or NR′R″;unsubstituted 3-11 membered heterocyclyl (e.g., 5-6 membered heteroarylcontaining 1 to 4 heteroatoms selected from O, N and S or 4-11 memberedheterocycloalkyl containing 1 to 4 heteroatoms selected from O, N andS); and 3-11 membered heterocyclyl (e.g., 5-6 membered heteroarylcontaining 1 to 4 heteroatoms selected from O, N and S or 4-11 memberedheterocycloalkyl containing 1 to 4 heteroatoms selected from O, N and S)substituted by halogen, OH, CN, unsubstituted C₁-C₆alkyl, unsubstitutedC₁-C₆ alkoxy, oxo or NR′R″. When R′ and R″ are attached to the samenitrogen atom, they can be combined with the nitrogen atom to form a 3-,4-, 5-, 6-, or 7-membered ring wherein a ring atom is optionallysubstituted with N, O or S and wherein the ring is optionallysubstituted with halogen, OH, CN, unsubstituted C₁-C₆alkyl,unsubstituted C₁-C₆ alkoxy, oxo or NR′R″. For example, —NR′R″ is meantto include 1-pyrrolidinyl and 4-morpholinyl.

The term “oxo” refers to ═O or (═O)₂.

As used herein a wavy line “

” that intersects a bond in a chemical structure indicate the point ofattachment of the atom to which the wavy bond is connected in thechemical structure to the remainder of a molecule, or to the remainderof a fragment of a molecule. In some embodiments, an arrow together withan asterisk is used in the manner of a wavy line to indicate a point ofattachment.

In certain embodiments, divalent groups are described genericallywithout specific bonding configurations. It is understood that thegeneric description is meant to include both bonding configurations,unless specified otherwise. For example, in the group R¹-R²-R³, if thegroup R² is described as —CH₂C(O)—, then it is understood that thisgroup can be bonded both as R¹—CH₂C(O)—R³, and as R¹—C(O)CH₂—R³, unlessspecified otherwise.

The terms “compound(s) of the invention,” and “compound(s) of thepresent invention” and the like, unless otherwise indicated, includecompounds of Formula (I) herein, such as compounds 1-18, sometimesreferred to as JAK inhibitors, including stereoisomers (includingatropisomers), geometric isomers, tautomers, solvates, metabolites,isotopes, salts (e.g., pharmaceutically acceptable salts), and prodrugsthereof. In some embodiments, solvates, metabolites, isotopes orprodrugs are excluded, or any combination thereof.

The phrase “pharmaceutically acceptable” refers to molecular entitiesand compositions that do not produce an adverse, allergic or otheruntoward reaction when administered to an animal, such as, for example,a human, as appropriate.

Compounds of the present invention may be in the form of a salt, such asa pharmaceutically acceptable salt. “Pharmaceutically acceptable salts”include both acid and base addition salts. “Pharmaceutically acceptableacid addition salt” refers to those salts which retain the biologicaleffectiveness and properties of the free bases and which are notbiologically or otherwise undesirable, formed with inorganic acids suchas hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid,carbonic acid, phosphoric acid and the like, and organic acids may beselected from aliphatic, cycloaliphatic, aromatic, araliphatic,heterocyclic, carboxylic, and sulfonic classes of organic acids such asformic acid, acetic acid, propionic acid, glycolic acid, gluconic acid,lactic acid, pyruvic acid, oxalic acid, malic acid, maleic acid,maloneic acid, succinic acid, fumaric acid, tartaric acid, citric acid,aspartic acid, ascorbic acid, glutamic acid, anthranilic acid, benzoicacid, cinnamic acid, mandelic acid, embonic acid, phenylacetic acid,methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid,p-toluenesulfonic acid, salicyclic acid and the like.

“Pharmaceutically acceptable base addition salts” include those derivedfrom inorganic bases such as sodium, potassium, lithium, ammonium,calcium, magnesium, iron, zinc, copper, manganese, aluminum salts andthe like. Particular base addition salts are the ammonium, potassium,sodium, calcium and magnesium salts. Salts derived from pharmaceuticallyacceptable organic nontoxic bases include salts of primary, secondary,and tertiary amines, substituted amines including naturally occurringsubstituted amines, cyclic amines and basic ion exchange resins, such asisopropylamine, trimethylamine, diethylamine, triethylamine,tripropylamine, ethanolamine, 2-diethylaminoethanol, tromethamine,dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine,hydrabamine, choline, betaine, ethylenediamine, glucosamine,methylglucamine, theobromine, purines, piperizine, piperidine,N-ethylpiperidine, polyamine resins and the like. Particular organicnon-toxic bases include isopropylamine, diethylamine, ethanolamine,tromethamine, dicyclohexylamine, choline, and caffeine.

In some embodiments, a salt is selected from a hydrochloride,hydrobromide, trifluoroacetate, sulphate, phosphate, acetate, fumarate,maleate, tartrate, lactate, citrate, pyruvate, succinate, oxalate,methanesulphonate, p-toluenesulphonate, bisulphate, benzenesulphonate,ethanesulphonate, malonate, xinafoate, ascorbate, oleate, nicotinate,saccharinate, adipate, formate, glycolate, palmitate, L-lactate,D-lactate, aspartate, malate, L-tartrate, D-tartrate, stearate, furoate(e.g., 2-furoate or 3-furoate), napadisylate(naphthalene-1,5-disulfonate or naphthalene-1-(sulfonicacid)-5-sulfonate), edisylate (ethane-1,2-disulfonate orethane-1-(sulfonic acid)-2-sulfonate), isethionate(2-hydroxyethylsulfonate), 2-mesitylenesulphonate,2-naphthalenesulphonate, 2,5-dichlorobenzenesulphonate, D-mandelate,L-mandelate, cinnamate, benzoate, adipate, esylate, malonate, mesitylate(2-mesitylenesulphonate), napsylate (2-naphthalenesulfonate), camsylate(camphor-10-sulphonate, for example (1S)-(+)-10-camphorsulfonic acidsalt), glutamate, glutarate, hippurate (2-(benzoylamino)acetate),orotate, xylate (p-xylene-2-sulphonate), and pamoic(2,2′-dihydroxy-1,1′-dinaphthylmethane-3,3′-dicarboxylate).

A “sterile” formulation is aseptic or free from all livingmicroorganisms and their spores.

“Stereoisomers” refer to compounds that have identical chemicalconstitution, but differ with regard to the arrangement of the atoms orgroups in space. Stereoisomers include diastereomers, enantiomers,conformers and the like.

“Chiral” refers to molecules which have the property ofnon-superimposability of the mirror image partner, while the term“achiral” refers to molecules which are superimposable on their mirrorimage partner.

“Diastereomer” refers to a stereoisomer with two or more centers ofchirality and whose molecules are not mirror images of one another.Diastereomers have different physical properties, e.g., melting points,boiling points, spectral properties or biological activities. Mixturesof diastereomers may separate under high resolution analyticalprocedures such as electrophoresis and chromatography such as HPLC.

“Enantiomers” refer to two stereoisomers of a compound which arenon-superimposable mirror images of one another.

Stereochemical definitions and conventions used herein generally followS. P. Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984)McGraw-Hill Book Company, New York; and Eliel, E. and Wilen, S.,“Stereochemistry of Organic Compounds”, John Wiley & Sons, Inc., NewYork, 1994. Many organic compounds exist in optically active forms,i.e., they have the ability to rotate the plane of plane-polarizedlight. In describing an optically active compound, the prefixes D and L,or R and S, are used to denote the absolute configuration of themolecule about its chiral center(s). The prefixes d and l or (+) and (−)are employed to designate the sign of rotation of plane-polarized lightby the compound, with (−) or l meaning that the compound islevorotatory. A compound prefixed with (+) or d is dextrorotatory. For agiven chemical structure, these stereoisomers are identical except thatthey are mirror images of one another. A specific stereoisomer may alsobe referred to as an enantiomer, and a mixture of such isomers is oftencalled an enantiomeric mixture. A 50:50 mixture of enantiomers isreferred to as a racemic mixture or a racemate, which may occur wherethere has been no stereoselection or stereospecificity in a chemicalreaction or process. The terms “racemic mixture” and “racemate” refer toan equimolar mixture of two enantiomeric species, devoid of opticalactivity.

The term “tautomer” or “tautomeric form” refers to structural isomers ofdifferent energies which are interconvertible via a low energy barrier.For example, proton tautomers (also known as prototropic tautomers)include interconversions via migration of a proton, such as keto-enoland imine-enamine isomerizations. Valence tautomers includeinterconversions by reorganization of some of the bonding electrons.

Certain compounds of the present invention can exist in unsolvated formsas well as solvated forms, including hydrated forms. A “solvate” refersto an association or complex of one or more solvent molecules and acompound of the present invention. Examples of solvents that formsolvates include water, isopropanol, ethanol, methanol, DMSO, ethylacetate, acetic acid, and ethanolamine. Certain compounds of the presentinvention can exist in multiple crystalline or amorphous forms. Ingeneral, all physical forms are intended to be within the scope of thepresent invention. The term “hydrate” refers to the complex where thesolvent molecule is water.

A “metabolite” refers to a product produced through metabolism in thebody of a specified compound or salt thereof. Such products can result,for example, from the oxidation, reduction, hydrolysis, amidation,deamidation, esterification, deesterification, enzymatic cleavage, andthe like, of the administered compound.

Metabolite products typically are identified by preparing aradiolabelled (e.g., ¹⁴C or ³H) isotope of a compound of the invention,administering it in a detectable dose (e.g., greater than about 0.5mg/kg) to an animal such as rat, mouse, guinea pig, monkey, or to ahuman, allowing sufficient time for metabolism to occur (typically about30 seconds to 30 hours) and isolating its conversion products from theurine, blood or other biological samples. These products are easilyisolated since they are labeled (others are isolated by the use ofantibodies capable of binding epitopes surviving in the metabolite). Themetabolite structures are determined in conventional fashion, e.g., byMS, LC/MS or NMR analysis. In general, analysis of metabolites is donein the same way as conventional drug metabolism studies well known tothose skilled in the art. The metabolite products, so long as they arenot otherwise found in vivo, are useful in diagnostic assays fortherapeutic dosing of the compounds of the invention.

A “subject,” “individual,” or “patient” is a vertebrate. In certainembodiments, the vertebrate is a mammal. Mammals include, but are notlimited to, farm animals (such as cows), sport animals, pets (such asguinea pigs, cats, dogs, rabbits and horses), primates, mice and rats.In certain embodiments, a mammal is a human. In embodiments comprisingadministration of a JAK inhibitor as described herein or apharmaceutically acceptable salt thereof to a patient, the patient maybe in need thereof.

The term “Janus kinase” refers to JAK1, JAK2, JAK3 and TYK2 proteinkinases. In some embodiments, a Janus kinase may be further defined asone of JAK1, JAK2, JAK3 or TYK2. In any embodiment, any one of JAK1,JAK2, JAK3 and TYK2 may be specifically excluded as a Janus kinase. Insome embodiments, a Janus kinase is JAK1. In some embodiments, a Januskinase is a combination of JAK1 and JAK2.

The terms “inhibiting” and “reducing,” or any variation of these terms,includes any measurable decrease or complete inhibition to achieve adesired result. For example, there may be a decrease of about, at mostabout, or at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%,50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99%, or more, or anyrange derivable therein, reduction of activity (e.g., JAK1 activity)compared to normal.

In some embodiments, a compound or a salt thereof (e.g., apharmaceutically acceptable salt thereof) described herein is selectivefor inhibition of JAK1 over JAK3 and TYK2. In some embodiments, acompound or a salt thereof (e.g., a pharmaceutically acceptable saltthereof) is selective for inhibition of JAK1 over JAK2, JAK3, or TYK2,or any combination of JAK2, JAK3, or TYK2. In some embodiments, acompound or a salt thereof (e.g., a pharmaceutically acceptable saltthereof) is selective for inhibition of JAK1 and JAK2 over JAK3 andTYK2. In some embodiments, a compound or a salt thereof (e.g., apharmaceutically acceptable salt thereof) is selective for inhibition ofJAK1 over JAK3. By “selective for inhibition” it is meant that thecompound or a salt thereof (e.g., a pharmaceutically acceptable saltthereof) is at least a 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%,55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99%, or more, or any rangederivable therein, better inhibitor of a particular Janus kinase (e.g.,JAK1) activity compared to another particular Janus kinase (e.g., JAK3)activity, or is at least a 2-, 3-, 4-, 5-, 10-, 25-, 50-, 100-, 250-, or500-fold better inhibitor of a particular Janus kinase (e.g., JAK1)activity compared to another particular Janus kinase (e.g., JAK3)activity.

“Therapeutically effective amount” means an amount of a compound or asalt thereof (e.g., a pharmaceutically acceptable salt thereof) of thepresent invention that (i) treats or prevents the particular disease,condition or disorder, or (ii) attenuates, ameliorates or eliminates oneor more symptoms of the particular disease, condition, or disorder, andoptionally (iii) prevents or delays the onset of one or more symptoms ofthe particular disease, condition or disorder described herein. In someembodiments, the therapeutically effective amount is an amountsufficient to decrease or alleviate the symptoms of an autoimmune orinflammatory disease (e.g., asthma). In some embodiments, atherapeutically effective amount is an amount of a chemical entitydescribed herein sufficient to significantly decrease the activity ornumber of B-cells. In the case of cancer, the therapeutically effectiveamount of the drug may reduce the number of cancer cells; reduce thetumor size; inhibit (i.e., slow to some extent and preferably stop)cancer cell infiltration into peripheral organs; inhibit (i.e., slow tosome extent and preferably stop) tumor metastasis; inhibit, to someextent, tumor growth; or relieve to some extent one or more of thesymptoms associated with the cancer. To the extent the drug may preventgrowth or kill existing cancer cells, it may be cytostatic or cytotoxic.For cancer therapy, efficacy can, for example, be measured by assessingthe time to disease progression (TTP) or determining the response rate(RR).

“Treatment” (and variations such as “treat” or “treating”) refers toclinical intervention in an attempt to alter the natural course of theindividual or cell being treated, and can be performed either forprophylaxis or during the course of clinical pathology. Desirableeffects of treatment include preventing occurrence or recurrence ofdisease, alleviation of symptoms, diminishment of any direct or indirectpathological consequences of the disease, stabilized (i.e., notworsening) state of disease, decreasing the rate of disease progression,amelioration or palliation of the disease state, prolonging survival ascompared to expected survival if not receiving treatment and remissionor improved prognosis. In some embodiments, a compound of the inventionor a salt thereof (e.g., a pharmaceutically acceptable salt thereof), isused to delay development of a disease or disorder or to slow theprogression of a disease or disorder. Those in need of treatment includethose already with the condition or disorder as well as those prone tohave the condition or disorder, (for example, through a geneticmutation) or those in which the condition or disorder is to beprevented.

“Inflammatory disorder” refers to any disease, disorder or syndrome inwhich an excessive or unregulated inflammatory response leads toexcessive inflammatory symptoms, host tissue damage, or loss of tissuefunction. “Inflammatory disorder” also refers to a pathological statemediated by influx of leukocytes or neutrophil chemotaxis.

“Inflammation” refers to a localized, protective response elicited byinjury or destruction of tissues, which serves to destroy, dilute, orwall off (sequester) both the injurious agent and the injured tissue.Inflammation is notably associated with influx of leukocytes orneutrophil chemotaxis. Inflammation can result from infection withpathogenic organisms and viruses and from noninfectious means such astrauma or reperfusion following myocardial infarction or stroke, immuneresponses to foreign antigens, and autoimmune responses. Accordingly,inflammatory disorders amenable to treatment with a compound or a saltthereof (e.g., a pharmaceutically acceptable salt thereof) of thepresent invention encompass disorders associated with reactions of thespecific defense system as well as with reactions of the nonspecificdefense system.

“Specific defense system” refers to the component of the immune systemthat reacts to the presence of specific antigens. Examples ofinflammation resulting from a response of the specific defense systeminclude the classical response to foreign antigens, autoimmune diseases,and delayed type hypersensitivity responses mediated by T-cells. Chronicinflammatory diseases, the rejection of solid transplanted tissue andorgans, e.g., kidney and bone marrow transplants, and graft versus hostdisease (GVHD), are further examples of inflammatory reactions of thespecific defense system.

The term “nonspecific defense system” refers to inflammatory disordersthat are mediated by leukocytes that are incapable of immunologicalmemory (e.g., granulocytes, and macrophages). Examples of inflammationthat result, at least in part, from a reaction of the nonspecificdefense system include inflammation associated with conditions such asadult (acute) respiratory distress syndrome (ARDS) or multiple organinjury syndromes; reperfusion injury; acute glomerulonephritis; reactivearthritis; dermatoses with acute inflammatory components; acute purulentmeningitis or other central nervous system inflammatory disorders suchas stroke; thermal injury; inflammatory bowel disease; granulocytetransfusion associated syndromes; and cytokine-induced toxicity.

“Autoimmune disease” refers to any group of disorders in which tissueinjury is associated with humoral or cell-mediated responses to thebody's own constituents. Non-limiting examples of autoimmune diseasesinclude rheumatoid arthritis, lupus and multiple sclerosis.

“Allergic disease” as used herein refers to any symptoms, tissue damage,or loss of tissue function resulting from allergy. “Arthritic disease”as used herein refers to any disease that is characterized byinflammatory lesions of the joints attributable to a variety ofetiologies. “Dermatitis” as used herein refers to any of a large familyof diseases of the skin that are characterized by inflammation of theskin attributable to a variety of etiologies. “Transplant rejection” asused herein refers to any immune reaction directed against graftedtissue, such as organs or cells (e.g., bone marrow), characterized by aloss of function of the grafted and surrounding tissues, pain, swelling,leukocytosis, and thrombocytopenia. The therapeutic methods of thepresent invention include methods for the treatment of disordersassociated with inflammatory cell activation.

“Inflammatory cell activation” refers to the induction by a stimulus(including, but not limited to, cytokines, antigens or auto-antibodies)of a proliferative cellular response, the production of solublemediators (including but not limited to cytokines, oxygen radicals,enzymes, prostanoids, or vasoactive amines), or cell surface expressionof new or increased numbers of mediators (including, but not limited to,major histocompatability antigens or cell adhesion molecules) ininflammatory cells (including but not limited to monocytes, macrophages,T lymphocytes, B lymphocytes, granulocytes (i.e., polymorphonuclearleukocytes such as neutrophils, basophils, and eosinophils), mast cells,dendritic cells, Langerhans cells, and endothelial cells). It will beappreciated by persons skilled in the art that the activation of one ora combination of these phenotypes in these cells can contribute to theinitiation, perpetuation, or exacerbation of an inflammatory disorder.

In some embodiments, inflammatory disorders which can be treatedaccording to the methods of this invention include, but are not limitedto, asthma, rhinitis (e.g., allergic rhinitis), allergic airwaysyndrome, atopic dermatitis, bronchitis, rheumatoid arthritis,psoriasis, contact dermatitis, chronic obstructive pulmonary disease(COPD) and delayed hypersensitivity reactions.

The terms “cancer” and “cancerous”, “neoplasm”, and “tumor” and relatedterms refer to or describe the physiological condition in mammals thatis typically characterized by unregulated cell growth. A “tumor”comprises one or more cancerous cells. Examples of cancer includecarcinoma, blastoma, sarcoma, seminoma, glioblastoma, melanoma,leukemia, and myeloid or lymphoid malignancies. More particular examplesof such cancers include squamous cell cancer (e.g., epithelial squamouscell cancer) and lung cancer including small-cell lung cancer, non-smallcell lung cancer (“NSCLC”), adenocarcinoma of the lung and squamouscarcinoma of the lung. Other cancers include skin, keratoacanthoma,follicular carcinoma, hairy cell leukemia, buccal cavity, pharynx(oral), lip, tongue, mouth, salivary gland, esophageal, larynx,hepatocellular, gastric, stomach, gastrointestinal, small intestine,large intestine, pancreatic, cervical, ovarian, liver, bladder,hepatoma, breast, colon, rectal, colorectal, genitourinary, biliarypassage, thyroid, papillary, hepatic, endometrial, uterine, salivarygland, kidney or renal, prostate, testis, vulval, peritoneum, anal,penile, bone, multiple myeloma, B-cell lymphoma, central nervous system,brain, head and neck, Hodgkin's, and associated metastases. Examples ofneoplastic disorders include myeloproliferative disorders, such aspolycythemia vera, essential thrombocytosis, myelofibrosis, such asprimary myelofibrosis, and chronic myelogenous leukemia (CML).

A “chemotherapeutic agent” is an agent useful in the treatment of agiven disorder, for example, cancer or inflammatory disorders. Examplesof chemotherapeutic agents are well-known in the art and includeexamples such as those disclosed in U.S. Publ. Appl. No. 2010/0048557,incorporated herein by reference. Additionally, chemotherapeutic agentsinclude pharmaceutically acceptable salts, acids or derivatives of anyof chemotherapeutic agents, as well as combinations of two or more ofthem.

“Package insert” is used to refer to instructions customarily includedin commercial packages of therapeutic products that contain informationabout the indications, usage, dosage, administration, contraindicationsor warnings concerning the use of such therapeutic products.

Unless otherwise stated, structures depicted herein include compoundsthat differ only in the presence of one or more isotopically enrichedatoms. Exemplary isotopes that can be incorporated into compounds of thepresent invention include isotopes of hydrogen, carbon, nitrogen,oxygen, phosphorus, sulfur, fluorine, chlorine, and iodine, such as ²H,³H, ¹¹C, ¹³C, ¹⁴C, ¹³N, ¹⁵N, ¹⁵O, ¹⁷O, ¹⁸O, ³²F, ³³F, ³⁵S, ¹⁸F, ³⁶Cl,¹²³I, and ¹²⁵I, respectively. Isotopically-labeled compounds (e.g.,those labeled with ³H and ¹⁴C) can be useful in compound or substratetissue distribution assays. Tritiated (i.e., ³H) and carbon-14 (i.e.,¹⁴C) isotopes can be useful for their ease of preparation anddetectability. Further, substitution with heavier isotopes such asdeuterium (i.e., ²H) may afford certain therapeutic advantages resultingfrom greater metabolic stability (e.g., increased in vivo half-life orreduced dosage requirements). In some embodiments, one or more hydrogenatoms are replaced by ²H or ³H, or one or more carbon atoms are replacedby ¹³C- or ¹⁴C-enriched carbon. Positron emitting isotopes such as ¹⁵O,¹³N, ¹¹C, and ¹⁸F are useful for positron emission tomography (PET)studies to examine substrate receptor occupancy. Isotopically labeledcompounds can generally be prepared by procedures analogous to thosedisclosed in the Schemes or in the Examples herein, by substituting anisotopically labeled reagent for a non-isotopically labeled reagent.

It is specifically contemplated that any limitation discussed withrespect to one embodiment of the invention may apply to any otherembodiment of the invention. Furthermore, any compound or a salt thereof(e.g., a pharmaceutically acceptable salt thereof) or composition of theinvention may be used in any method of the invention, and any method ofthe invention may be used to produce or to utilize any compound or asalt thereof (e.g., a pharmaceutically acceptable salt thereof) orcomposition of the invention.

The use of the term “or” is used to mean “and/or” unless explicitlyindicated to refer to alternatives only or the alternatives are mutuallyexclusive, although the disclosure supports a definition that refers toonly alternatives and “and/or.”

Throughout this application, the term “about” is used to indicate that avalue includes the standard deviation of error for the device or methodbeing employed to determine the value.

As used herein, “a” or “an” means one or more, unless clearly indicatedotherwise. As used herein, “another” means at least a second or more.

Headings used herein are intended only for organizational purposes.

Inhibitors of Janus Kinases

One embodiment provides a compound of Formula (I):

or a salt (e.g., a pharmaceutically acceptable salt) thereof, wherein:

R¹ is hydrogen or CH₃;

R² is halogen, C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₃-C₆cycloalkyl,or —OR^(a), wherein R² is optionally substituted by one or more groupsindependently selected from the group consisting of halogen, C₁-C₃alkyl,cyano, hydroxy and oxo;

R^(a) is C₁-C₆alkyl, -phenyl-COR^(b)R^(c), -phenyl-(3-6-memberedheterocyclyl), or 3-11-membered heterocyclyl, wherein R^(a) isoptionally substituted by one or more groups independently selected fromthe group consisting of halogen, C₁-C₃alkyl, cyano, hydroxy and oxo;

R^(b) and R^(c) are each independently hydrogen or CH₃;

R³ is hydrogen or NH₂;

R⁴ is hydrogen or CH₃; and

R⁵ is hydrogen or NH₂.

In some embodiments, R¹ is hydrogen. In some embodiments, R¹ is CH₃. Insome embodiments, R³ is hydrogen. In some embodiments, R⁴ and R⁵ areeach hydrogen. In some embodiments, R¹, R³, R⁴ and R⁵ are each hydrogen.

In some embodiments, R² is selected from the group consisting ofhalogen, C₁-C₆haloalkyl, and C₁-C₆haloalkyoxy. In some embodiments, R²is selected from the group consisting of

In some embodiments, a compound selected from 1-18 below is provided, ora salt (e.g., a pharmaceutically acceptable salt) or stereoisomerthereof:

In some embodiments, the following compound is provided:

or a salt (e.g., a pharmaceutically acceptable salt) thereof.

In some embodiments, the following compound is provided:

or a salt (e.g., a pharmaceutically acceptable salt) thereof.

In some embodiments, the following compound is provided:

or a salt (e.g., a pharmaceutically acceptable salt) thereof.

In some embodiments, the following compound is provided:

or a salt (e.g., a pharmaceutically acceptable salt) or stereoisomerthereof.

In some embodiments, the following compound is provided:

or a salt (e.g., a pharmaceutically acceptable salt) thereof.

In some embodiments, the following compound is provided:

or a salt (e.g., a pharmaceutically acceptable salt) or stereoisomerthereof.

In some embodiments, the following compound is provided:

or a salt (e.g., a pharmaceutically acceptable salt) thereof.

In some embodiments, the following compound is provided:

or a salt (e.g., a pharmaceutically acceptable salt) thereof.

In some embodiments, the following compound is provided:

or a salt (e.g., a pharmaceutically acceptable salt) or stereoisomerthereof.

In some embodiments, the following compound is provided:

or a salt (e.g., a pharmaceutically acceptable salt) or stereoisomerthereof.

In some embodiments, the following compound is provided:

or a salt (e.g., a pharmaceutically acceptable salt) thereof.

In some embodiments, the following compound is provided:

or a salt (e.g., a pharmaceutically acceptable salt) thereof.

In some embodiments, the following compound is provided:

or a salt (e.g., a pharmaceutically acceptable salt) thereof.

In some embodiments, the following compound is provided:

or a salt (e.g., a pharmaceutically acceptable salt) thereof.

In some embodiments, the following compound is provided:

or a salt (e.g., a pharmaceutically acceptable salt) thereof.

In some embodiments, the following compound is provided:

or a salt (e.g., a pharmaceutically acceptable salt) thereof.

In some embodiments, a compound selected from (a)-(v) below is provided,or a salt (e.g., a pharmaceutically acceptable salt) or stereoisomerthereof:

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Also provided is a pharmaceutical composition comprising a JAK inhibitoras described herein, or a pharmaceutically acceptable salt thereof, anda pharmaceutically acceptable carrier, dilient or excipient.

Also provided is the use of a JAK inhibitor as described herein, or apharmaceutically acceptable salt thereof in therapy, such as in thetreatment of an inflammatory disease (e.g., asthma). Also provided isthe use of a JAK inhibitor as described herein or a pharmaceuticallyacceptable salt thereof for the preparation of a medicament for thetreatment of an inflammatory disease. Also provided is a method ofpreventing, treating or lessening the severity of a disease or conditionresponsive to the inhibition of a Janus kinase activity in a patient,comprising administering to the patient a therapeutically effectiveamount of a JAK inhibitor as described herein or a pharmaceuticallyacceptable salt thereof.

In one embodiment the disease or condition for therapy is cancer,polycythemia vera, essential thrombocytosis, myelofibrosis, chronicmyelogenous leukemia (CML), rheumatoid arthritis, inflammatory bowelsyndrome, Crohn's disease, psoriasis, contact dermatitis or delayedhypersensitivity reactions.

In one embodiment the use of a JAK inhibitor as described herein or apharmaceutically acceptable salt thereof, for the treatment of cancer,polycythemia vera, essential thrombocytosis, myelofibrosis, chronicmyelogenous leukemia (CML), rheumatoid arthritis, inflammatory bowelsyndrome, Crohn's disease, psoriasis, contact dermatitis or delayedhypersensitivity reactions is provided.

In one embodiment a composition that is formulated for administration byinhalation is provided.

In one embodiment a metered dose inhaler that comprises a compound ofthe present invention or a pharmaceutically acceptable salt thereof isprovided.

In one embodiment a JAK inhibitor as described herein or apharmaceutically acceptable salt thereof is at least five-times morepotent as an inhibitor of JAK1 than as an inhibitor of LRRK2.

In one embodiment a JAK inhibitor as described herein or apharmaceutically acceptable salt thereof is at least ten-times morepotent as an inhibitor of JAK1 than as an inhibitor of LRRK2.

In one embodiment a JAK inhibitor as described herein or apharmaceutically acceptable salt thereof is at least five-times morepotent as an inhibitor of JAK1 than as an inhibitor of JAK2.

In one embodiment a JAK inhibitor as described herein or apharmaceutically acceptable salt thereof is at least ten-times morepotent as an inhibitor of JAK1 than as an inhibitor of JAK2.

In one embodiment a JAK inhibitor as described herein or apharmaceutically acceptable salt thereof is at least five-times morepotent as an inhibitor of JAK1 than as an inhibitor of JAK3.

In one embodiment a JAK inhibitor as described herein or apharmaceutically acceptable salt thereof is at least ten-times morepotent as an inhibitor of JAK1 than as an inhibitor of JAK3.

In one embodiment a JAK inhibitor as described herein or apharmaceutically acceptable salt thereof is at least five-times morepotent as an inhibitor of JAK1 than as an inhibitor of TYK2.

In one embodiment a JAK inhibitor as described herein or apharmaceutically acceptable salt thereof is at least ten-times morepotent as an inhibitor of JAK1 than as an inhibitor of TYK2.

In one embodiment a method for treating hair loss in a mammal comprisingadministering a JAK inhibitor as described herein or a pharmaceuticallyacceptable salt thereof to the mammal is provided.

In one embodiment the use of a JAK inhibitor as described herein or apharmaceutically acceptable salt thereof for the treatment of hair lossis provided.

In one embodiment the use of a JAK inhibitor as described herein or apharmaceutically acceptable salt thereof to prepare a medicament fortreating hair loss in a mammal is provided.

Compounds of the invention may contain one or more asymmetric carbonatoms. Accordingly, the compounds may exist as diastereomers,enantiomers or mixtures thereof. The syntheses of the compounds mayemploy racemates, diastereomers or enantiomers as starting materials oras intermediates. Mixtures of particular diastereomeric compounds may beseparated, or enriched in one or more particular diastereomers, bychromatographic or crystallization methods. Similarly, enantiomericmixtures may be separated, or enantiomerically enriched, using the sametechniques or others known in the art. Each of the asymmetric carbon ornitrogen atoms may be in the R or S configuration and both of theseconfigurations are within the scope of the invention.

In the structures shown herein, where the stereochemistry of anyparticular chiral atom is not specified, then all stereoisomers arecontemplated and included as the compounds of the invention. Wherestereochemistry is specified by a solid wedge or dashed linerepresenting a particular configuration, then that stereoisomer is sospecified and defined. Unless otherwise specified, if solid wedges ordashed lines are used, relative stereochemistry is intended.

Another aspect includes prodrugs of the compounds described herein,including known amino-protecting and carboxy-protecting groups which arereleased, for example hydrolyzed, to yield the compound of the presentinvention under physiologic conditions.

The term “prodrug” refers to a precursor or derivative form of apharmaceutically active substance that is less efficacious to thepatient compared to the parent drug and is capable of beingenzymatically or hydrolytically activated or converted into the moreactive parent form. See, e.g., Wilman, “Prodrugs in Cancer Chemotherapy”Biochemical Society Transactions, 14, pp. 375-382, 615th Meeting Belfast(1986) and Stella et al., “Prodrugs: A Chemical Approach to TargetedDrug Delivery,” Directed Drug Delivery, Borchardt et al., (ed.), pp.247-267, Humana Press (1985). Prodrugs include, but are not limited to,phosphate-containing prodrugs, thiophosphate-containing prodrugs,sulfate-containing prodrugs, peptide-containing prodrugs, D-aminoacid-modified prodrugs, glycosylated prodrugs, β-lactam-containingprodrugs, optionally substituted phenoxyacetamide-containing prodrugs oroptionally substituted phenylacetamide-containing prodrugs, and5-fluorocytosine and 5-fluorouridine prodrugs.

A particular class of prodrugs are compounds in which a nitrogen atom inan amino, amidino, aminoalkyleneamino, iminoalkyleneamino or guanidinogroup is substituted with a hydroxy group, an alkylcarbonyl (—CO—R)group, an alkoxycarbonyl (—CO—OR), or an acyloxyalkyl-alkoxycarbonyl(—CO—O—R—O—CO—R) group where R is a monovalent or divalent group, forexample alkyl, alkylene or aryl, or a group having the Formula—C(O)—O-CP1P2-haloalkyl, where P1 and P2 are the same or different andare hydrogen, alkyl, alkoxy, cyano, halogen, alkyl or aryl. In aparticular embodiment, the nitrogen atom is one of the nitrogen atoms ofthe amidino group. Prodrugs may be prepared by reacting a compound withan activated group, such as acyl groups, to bond, for example, anitrogen atom in the compound to the exemplary carbonyl of the activatedacyl group. Examples of activated carbonyl compounds are thosecontaining a leaving group bonded to the carbonyl group, and include,for example, acyl halides, acyl amines, acyl pyridinium salts, acylalkoxides, acyl phenoxides such as p-nitrophenoxy acyl, dinitrophenoxyacyl, fluorophenoxy acyl, and difluorophenoxy acyl. The reactions aregenerally carried out in inert solvents at reduced temperatures such as−78° C. to about 50° C. The reactions may also be carried out in thepresence of an inorganic base, for example potassium carbonate or sodiumbicarbonate, or an organic base such as an amine, including pyridine,trimethylamine, triethylamine, triethanolamine, or the like.

Additional types of prodrugs are also encompassed. For instance, a freecarboxyl group of a JAK inhibitor as described herein can be derivatizedas an amide or alkyl ester. As another example, compounds of the presentinvention comprising free hydroxy groups can be derivatized as prodrugsby converting the hydroxy group into a group such as, but not limitedto, a phosphate ester, hemisuccinate, dimethylaminoacetate, orphosphoryloxymethyloxycarbonyl group, as outlined in Fleisher, D. etal., (1996) Improved oral drug delivery: solubility limitations overcomeby the use of prodrugs Advanced Drug Delivery Reviews, 19:115. Carbamateprodrugs of hydroxy and amino groups are also included, as are carbonateprodrugs, sulfonate esters and sulfate esters of hydroxy groups.Derivatization of hydroxy groups as (acyloxy)methyl and (acyloxy)ethylethers, wherein the acyl group can be an alkyl ester optionallysubstituted with groups including, but not limited to, ether, amine andcarboxylic acid functionalities, or where the acyl group is an aminoacid ester as described above, are also encompassed. Prodrugs of thistype are described in J. Med. Chem., (1996), 39:10. More specificexamples include replacement of the hydrogen atom of the alcohol groupwith a group such as (C₁-C₆)alkanoyloxymethyl,1-((C₁-C₆)alkanoyloxy)ethyl, 1-methyl-1-((C₁-C₆)alkanoyloxy)ethyl,(C₁-C₆)alkoxycarbonyloxymethyl, N—(C₁-C₆)alkoxycarbonylaminomethyl,succinoyl, (C₁-C₆)alkanoyl, alpha-amino(C₁-C₄)alkanoyl, arylacyl andalpha-aminoacyl, or alpha-aminoacyl-alpha-aminoacyl, where eachalpha-aminoacyl group is independently selected from the naturallyoccurring L-amino acids, P(O)(OH)₂, —P(O)(O(C₁-C₆)alkyl)₂ or glycosyl(the radical resulting from the removal of a hydroxyl group of thehemiacetal form of a carbohydrate).

“Leaving group” refers to a portion of a first reactant in a chemicalreaction that is displaced from the first reactant in the chemicalreaction. Examples of leaving groups include, but are not limited to,halogen atoms, alkoxy and sulfonyloxy groups. Example sulfonyloxy groupsinclude, but are not limited to, alkylsulfonyloxy groups (for examplemethyl sulfonyloxy (mesylate group) and trifluoromethylsulfonyloxy(triflate group)) and arylsulfonyloxy groups (for examplep-toluenesulfonyloxy (tosylate group) and p-nitrosulfonyloxy (nosylategroup)).

Synthesis of Janus Kinase Inhibitor Compounds

Compounds may be synthesized by synthetic routes described herein. Incertain embodiments, processes well-known in the chemical arts can beused, in addition to, or in light of, the description contained herein.The starting materials are generally available from commercial sourcessuch as Aldrich Chemicals (Milwaukee, Wis.) or are readily preparedusing methods well known to those skilled in the art (e.g., prepared bymethods generally described in Louis F. Fieser and Mary Fieser, Reagentsfor Organic Synthesis, v. 1-19, Wiley, N.Y. (1967-1999 ed.), BeilsteinsHandbuch der organischen Chemie, 4, Aufl. ed. Springer-Verlag, Berlin,including supplements (also available via the Beilstein onlinedatabase)), or Comprehensive Heterocyclic Chemistry, Editors Katrizkyand Rees, Pergamon Press, 1984.

Compounds may be prepared singly or as compound libraries comprising atleast 2, for example 5 to 1,000 compounds, or 10 to 100 compounds.Libraries of compounds may be prepared by a combinatorial ‘split andmix’ approach or by multiple parallel syntheses using either solutionphase or solid phase chemistry, by procedures known to those skilled inthe art. Thus according to a further aspect of the invention there isprovided a compound library comprising at least 2 compounds of thepresent invention.

For illustrative purposes, reaction Schemes depicted below provideroutes for synthesizing the compounds of the present invention as wellas key intermediates. For a more detailed description of the individualreaction steps, see the Examples section below. Those skilled in the artwill appreciate that other synthetic routes may be used. Although somespecific starting materials and reagents are depicted in the Schemes anddiscussed below, other starting materials and reagents can besubstituted to provide a variety of derivatives or reaction conditions.In addition, many of the compounds prepared by the methods describedbelow can be further modified in light of this disclosure usingconventional chemistry well known to those skilled in the art.

In the preparation of compounds of the present invention, protection ofremote functionality (e.g., primary or secondary amine) of intermediatesmay be necessary. The need for such protection will vary depending onthe nature of the remote functionality and the conditions of thepreparation methods. Suitable amino-protecting groups include acetyl,trifluoroacetyl, benzyl, phenylsulfonyl, t-butoxycarbonyl (BOC),benzyloxycarbonyl (CBz) and 9-fluorenylmethyleneoxycarbonyl (Fmoc). Theneed for such protection is readily determined by one skilled in theart. For a general description of protecting groups and their use, seeT. W. Greene, Protective Groups in Organic Synthesis, John Wiley & Sons,New York, 1991.

Other conversions commonly used in the synthesis of compounds of thepresent invention, and which can be carried out using a variety ofreagents and conditions, include the following:

-   (1) Reaction of a carboxylic acid with an amine to form an amide.    Such a transformation can be achieved using various reagents known    to those skilled in the art but a comprehensive review can be found    in Tetrahedron, 2005, 61, 10827-10852.-   (2) Reaction of a primary or secondary amine with an aryl halide or    pseudo halide, e.g., a triflate, commonly known as a    “Buchwald-Hartwig cross-coupling,” can be achieved using a variety    of catalysts, ligands and bases. A review of these methods is    provided in Comprehensive Organic Name Reactions and Reagents, 2010,    575-581.-   (3) A palladium cross-coupling reaction between an aryl halide and a    vinyl boronic acid or boronate ester. This transformation is a type    of “Suzuki-Miyaura cross-coupling,” a class of reaction that has    been thoroughly reviewed in Chemical Reviews, 1995, 95(7),    2457-2483.-   (4) The hydrolysis of an ester to give the corresponding carboxylic    acid is well known to those skilled in the art and conditions    include: for methyl and ethyl esters, the use of a strong aqueous    base such as lithium, sodium or potassium hydroxide or a strong    aqueous mineral acid such as HCl; for a tert-butyl ester, hydrolysis    would be carried out using acid, for example, HCl in dioxane or    trifluoroacetic acid (TFA) in dichloromethane (DCM).

Reaction Scheme 1 illustrates a synthesis for compounds 6, 8 and 10therein. Compound 1 can be arylated with4-bromo-1-(difluoromethoxy)-2-iodobenzene under palladium catalyzedconditions to generate compound 2. The nitro group of compound 2 can bereduced with conditions such as iron and ammonium chloride to generateamino aniline 3. Amide bond coupling with commercially availablepyrazolo[1,5-a]pyrimidine-3-carboxylic acid in the presence of acoupling reagent such as, but not limited to, PyAOP, with an organicbase such as, but not limited to DIPEA, and DMAP in an organic solventsuch as, but not limited to, DMF provides compound 4. Compound 4 can beconverted to the corresponding iodide 5 using conditions such as sodiumiodide and CuI with a base such as N,N-dimethylethane-1,2-diamine in asolvent such as tBuOH. Compounds of formula 7 may be formed fromtreatment of compound 4 with a substituted boronic acid (or ester) orBF₃K salt under palladium catalyzed conditions with a base such as, butnot limited to, cesium carbonate in a solvent such as, but not limitedto, 1,4-dioxane. Additionally, compounds of formula 9 may be synthesizedby treatment of compound 4 with an appropriately substituted phenolunder Pd catalyzed coupling conditions with a base, such as, but notlimited to, cesium carbonate in a solvent such as, but not limited to,toluene. Removal of the SEM protecting group of compounds of formulas 5,7 and 9 to generate compounds of formulas 6, 8 and 10 can beaccomplished with an acid such as, but not limited to HCl in a solventsuch as, but not limited to, 1,4-dioxane.

Reaction Scheme 2 illustrates a synthesis for compounds of FormulasI-III therein. Compounds of formulas 6, 8 and 10 can be treated with anappropriately substituted 2-bromo-N,N-dimethylacetamide with a base suchas, but not limited to, cesium carbonate in a solvent such as, but notlimited to, DMF to afford compounds of Formulas I-III.

Reaction Scheme 3 illustrates a synthesis for compounds of FormulasIV-VI therein. Compounds of Formula II (R₁═Br) can be treated with anappropriately substituted phenol under Pd catalyzed coupling conditionswith a base, such as, but not limited to, cesium carbonate in a solventsuch as, but not limited to, toluene to afford compounds of Formula IV.Compounds of Formula V can be obtained from treatment of compound 4 witha substituted boronic acid (or ester) or BF₃K salt under palladiumcatalyzed conditions with an base such as, but not limited to, cesiumcarbonate in a solvent such as, but not limited to, 1,4-dioxane.Difluoromethyl compounds of Formula VI can be obtained using methodsdescribed in J. Am. Chem. Soc., 2014, 136, 4149-4152. Additionally, whenR₁ of compounds of Formula V is an appropriately substituted olefin,further manipulation of this olefin using standard methods can beaccomplished to furnish fluorinated alkanes.

Reaction Scheme 4 illustrates a synthesis for compounds of Formula VIItherein. Commercially available 4-(difluoromethoxy)phenol can be treatedwith a brominating agent such as, but not limited to, NBS in a solventsuch as, but not limited, acetic acid to yield 12. Difluoromethylationof 12 to form compound 13 can be accomplished by treatment of compound12 with diethyl (bromodifluoromethyl)phosphonate with a base such as,but not limited to, aqueous potassium hydroxide in a solvent such as,but not limited to, acetonitrile. Compound 13 can be treated with4-nitro-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-pyrazole4-bromo-1-(difluoromethoxy)-2-iodobenzene under palladium catalyzedconditions with a base such as, but not limited to, potassium carbonatein a solvent such as, but not limited to, DMA to generate compound 14.The nitro group of compound 14 can be reduced with conditions such asiron and ammonium chloride to generate amino aniline 15. Amide bondcoupling of compound 15 with commercially availablepyrazolo[1,5-a]pyrimidine-3-carboxylic acid in the presence of acoupling reagent such as, but not limited to, PyAOP, with an organicbase such as, but not limited to, DIPEA and DMAP in a solvent such as,but not limited to, DMF provides compound 16. Removal of the SEMprotecting group of compound 16 can be accomplished with an acid suchas, but not limited to, HCl in an organic solvent such as, but notlimited to, 1,4-dioxane to generate compounds of Formula VII.

Reaction Scheme 5 illustrates a synthesis for compounds of Formula VIIItherein. Compound 17 can be treated with 2-bromo-N,N-dimethylacetamidewith a base such as, but not limited to, cesium carbonate in a solventsuch as, but not limited to, DMF to afford compound 18. Removal of theBoc protecting group of compound 18 can be accomplished with an acidsuch as, but not limited to, HCl in an organic solvent such as, but notlimited to, 1,4-dioxane to generate compounds of Formula VIII.

It will be appreciated that where appropriate functional groups exist,compounds of various formulae or any intermediates used in theirpreparation may be further derivatised by one or more standard syntheticmethods employing condensation, substitution, oxidation, reduction, orcleavage reactions. Particular substitution approaches includeconventional alkylation, arylation, heteroarylation, acylation,sulfonylation, halogenation, nitration, formylation and couplingprocedures.

In a further example, primary amine or secondary amine groups may beconverted into amide groups (—NHCOR′ or —NRCOR′) by acylation. Acylationmay be achieved by reaction with an appropriate acid chloride in thepresence of a base, such as triethylamine, in a suitable solvent, suchas dichloromethane, or by reaction with an appropriate carboxylic acidin the presence of a suitable coupling agent such HATU(O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate) in a suitable solvent such as dichloromethane.Similarly, amine groups may be converted into sulphonamide groups(—NHSO₂R′ or —NR″SO₂R′) groups by reaction with an appropriate sulphonylchloride in the presence of a suitable base, such as triethylamine, in asuitable solvent such as dichloromethane. Primary or secondary aminegroups can be converted into urea groups (—NHCONR′R″ or —NRCONR′R″) byreaction with an appropriate isocyanate in the presence of a suitablebase such as triethylamine, in a suitable solvent, such asdichloromethane.

An amine (—NH₂) may be obtained by reduction of a nitro (—NO₂) group,for example by catalytic hydrogenation, using for example hydrogen inthe presence of a metal catalyst, for example palladium on a supportsuch as carbon in a solvent such as ethyl acetate or an alcohol e.g.,methanol. Alternatively, the transformation may be carried out bychemical reduction using for example a metal, e.g., tin or iron, in thepresence of an acid such as hydrochloric acid.

In a further example, amine (—CH₂NH₂) groups may be obtained byreduction of nitriles (—CN), for example by catalytic hydrogenationusing for example hydrogen in the presence of a metal catalyst, forexample palladium on a support such as carbon, or Raney nickel, in asolvent such as an ether e.g., a cyclic ether such as tetrahydrofuran,at an appropriate temperature, for example from about −78° C. to thereflux temperature of the solvent.

In a further example, amine (—NH₂) groups may be obtained fromcarboxylic acid groups (—CO₂H) by conversion to the corresponding acylazide (—CON₃), Curtius rearrangement and hydrolysis of the resultantisocyanate (—N═C═O).

Aldehyde groups (—CHO) may be converted to amine groups (—CH₂NR′R″)) byreductive amination employing an amine and a borohydride, for examplesodium triacetoxyborohydride or sodium cyanoborohydride, in a solventsuch as a halogenated hydrocarbon, for example dichloromethane, or analcohol such as ethanol, where necessary in the presence of an acid suchas acetic acid at around ambient temperature.

In a further example, aldehyde groups may be converted into alkenylgroups (—CH═CHR′) by the use of a Wittig or Wadsworth-Emmons reactionusing an appropriate phosphorane or phosphonate under standardconditions known to those skilled in the art.

Aldehyde groups may be obtained by reduction of ester groups (such as—CO₂Et) or nitriles (—CN) using diisobutylaluminium hydride in asuitable solvent such as toluene. Alternatively, aldehyde groups may beobtained by the oxidation of alcohol groups using any suitable oxidisingagent known to those skilled in the art.

Ester groups (—CO₂R′) may be converted into the corresponding acid group(—CO₂H) by acid- or base-catalused hydrolysis, depending on the natureof R. If R is t-butyl, acid-catalysed hydrolysis can be achieved forexample by treatment with an organic acid such as trifluoroacetic acidin an aqueous solvent, or by treatment with an inorganic acid such ashydrochloric acid in an aqueous solvent.

Carboxylic acid groups (—CO₂H) may be converted into amides (CONHR′ or—CONR′R″) by reaction with an appropriate amine in the presence of asuitable coupling agent, such as HATU, in a suitable solvent such asdichloromethane.

In a further example, carboxylic acids may be homologated by one carbon(i.e CO₂H to —CH₂CO₂H) by conversion to the corresponding acid chloride(—COCl) followed by Arndt-Eistert synthesis.

In a further example, —OH groups may be generated from the correspondingester (e.g., —CO₂R′), or aldehyde (—CHO) by reduction, using for examplea complex metal hydride such as lithium aluminium hydride in diethylether or tetrahydrofuran, or sodium borohydride in a solvent such asmethanol. Alternatively, an alcohol may be prepared by reduction of thecorresponding acid (—CO₂H), using for example lithium aluminium hydridein a solvent such as tetrahydrofuran, or by using borane in a solventsuch as tetrahydrofuran.

Alcohol groups may be converted into leaving groups, such as halogenatoms or sulfonyloxy groups such as an alkylsulfonyloxy, e.g.,trifluoromethylsulfonyloxy or arylsulfonyloxy, e.g.,p-toluenesulfonyloxy group using conditions known to those skilled inthe art. For example, an alcohol may be reacted with thioyl chloride ina halogenated hydrocarbon (e.g., dichloromethane) to yield thecorresponding chloride. A base (e.g., triethylamine) may also be used inthe reaction.

In another example, alcohol, phenol or amide groups may be alkylated bycoupling a phenol or amide with an alcohol in a solvent such astetrahydrofuran in the presence of a phosphine, e.g., triphenylphosphineand an activator such as diethyl-, diisopropyl, ordimethylazodicarboxylate. Alternatively alkylation may be achieved bydeprotonation using a suitable base e.g., sodium hydride followed bysubsequent addition of an alkylating agent, such as an alkyl halide.

Aromatic halogen substituents in the compounds may be subjected tohalogen-metal exchange by treatment with a base, for example a lithiumbase such as n-butyl or t-butyl lithium, optionally at a lowtemperature, e.g., around −78° C., in a solvent such as tetrahydrofuran,and then quenched with an electrophile to introduce a desiredsubstituent. Thus, for example, a formyl group may be introduced byusing N,N-dimethylformamide as the electrophile. Aromatic halogensubstituents may alternatively be subjected to metal (e.g., palladium orcopper) catalysed reactions, to introduce, for example, acid, ester,cyano, amide, aryl, heteraryl, alkenyl, alkynyl, thio- or aminosubstituents. Suitable procedures which may be employed include thosedescribed by Heck, Suzuki, Stille, Buchwald or Hartwig.

Aromatic halogen substituents may also undergo nucleophilic displacementfollowing reaction with an appropriate nucleophile such as an amine oran alcohol. Advantageously, such a reaction may be carried out atelevated temperature in the presence of microwave irradiation.

Methods of Separation

In each of the exemplary Schemes it may be advantageous to separatereaction products from one another or from starting materials. Thedesired products of each step or series of steps is separated orpurified (hereinafter separated) to the desired degree of homogeneity bythe techniques common in the art. Typically such separations involvemultiphase extraction, crystallization or trituration from a solvent orsolvent mixture, distillation, sublimation, or chromatography.Chromatography can involve any number of methods including, for example:reverse-phase and normal phase; size exclusion; ion exchange;supercritical fluid; high, medium, and low pressure liquidchromatography methods and apparatus; small scale analytical; simulatedmoving bed (SMB) and preparative thin or thick layer chromatography, aswell as techniques of small scale thin layer and flash chromatography.

Another class of separation methods involves treatment of a mixture witha reagent selected to bind to or render otherwise separable a desiredproduct, unreacted starting material, reaction by product, or the like.Such reagents include adsorbents or absorbents such as activated carbon,molecular sieves, ion exchange media, or the like. Alternatively, thereagents can be acids in the case of a basic material, bases in the caseof an acidic material, binding reagents such as antibodies, bindingproteins, selective chelators such as crown ethers, liquid/liquid ionextraction reagents (LIX), or the like.

Selection of appropriate methods of separation depends on the nature ofthe materials involved. Example separation methods include boilingpoint, and molecular weight in distillation and sublimation, presence orabsence of polar functional groups in chromatography, stability ofmaterials in acidic and basic media in multiphase extraction, and thelike. One skilled in the art will apply techniques most likely toachieve the desired separation.

Diastereomeric mixtures can be separated into their individualdiastereoisomers on the basis of their physical chemical differences bymethods well known to those skilled in the art, such as bychromatography or fractional crystallization. Enantiomers can beseparated by converting the enantiomeric mixture into a diastereomericmixture by reaction with an appropriate optically active compound (e.g.,chiral auxiliary such as a chiral alcohol or Mosher's acid chloride),separating the diastereoisomers and converting (e.g., hydrolyzing) theindividual diastereoisomers to the corresponding pure enantiomers. Also,some of the compounds of the present invention may be atropisomers(e.g., substituted biaryls) and are considered as part of thisinvention. Enantiomers can also be separated by use of a chiral HPLCcolumn or supercritical fluid chromatography.

A single stereoisomer, e.g., an enantiomer, substantially free of itsstereoisomer may be obtained by resolution of the racemic mixture usinga method such as formation of diastereomers using optically activeresolving agents (Eliel, E. and Wilen, S., Stereochemistry of OrganicCompounds, John Wiley & Sons, Inc., New York, 1994; Lochmuller, C. H.,J. Chromatogr., 113(3):283-302 (1975)). Racemic mixtures of chiralcompounds of the invention can be separated and isolated by any suitablemethod, including: (1) formation of ionic, diastereomeric salts withchiral compounds and separation by fractional crystallization or othermethods, (2) formation of diastereomeric compounds with chiralderivatizing reagents, separation of the diastereomers, and conversionto the pure stereoisomers, and (3) separation of the substantially pureor enriched stereoisomers directly under chiral conditions. See: DrugStereochemistry, Analytical Methods and Pharmacology, Irving W. Wainer,Ed., Marcel Dekker, Inc., New York (1993).

Diastereomeric salts can be formed by reaction of enantiomerically purechiral bases such as brucine, quinine, ephedrine, strychnine,α-methyl-β-phenylethylamine (amphetamine), and the like with asymmetriccompounds bearing acidic functionality, such as carboxylic acid andsulfonic acid. The diastereomeric salts may be induced to separate byfractional crystallization or ionic chromatography. For separation ofthe optical isomers of amino compounds, addition of chiral carboxylic orsulfonic acids, such as camphorsulfonic acid, tartaric acid, mandelicacid, or lactic acid can result in formation of the diastereomericsalts.

Alternatively, the substrate to be resolved is reacted with oneenantiomer of a chiral compound to form a diastereomeric pair (Eliel, E.and Wilen, S., Stereochemistry of Organic Compounds, John Wiley & Sons,Inc., New York, 1994, p. 322). Diastereomeric compounds can be formed byreacting asymmetric compounds with enantiomerically pure chiralderivatizing reagents, such as menthyl derivatives, followed byseparation of the diastereomers and hydrolysis to yield the pure orenriched enantiomer. A method of determining optical purity involvesmaking chiral esters, such as a menthyl ester, e.g., (−) menthylchloroformate in the presence of base, or Mosher ester,α-methoxy-α-(trifluoromethyl)phenyl acetate (Jacob, J. Org. Chem.47:4165 (1982)), of the racemic mixture, and analyzing the NMR spectrumfor the presence of the two atropisomeric enantiomers or diastereomers.Stable diastereomers of atropisomeric compounds can be separated andisolated by normal- and reverse-phase chromatography following methodsfor separation of atropisomeric naphthyl-isoquinolines (WO 96/15111,incorporated herein by reference). By method (3), a racemic mixture oftwo enantiomers can be separated by chromatography using a chiralstationary phase (Chiral Liquid Chromatography W. J. Lough, Ed., Chapmanand Hall, New York, (1989); Okamoto, J. of Chromatogr. 513:375-378(1990)). Enriched or purified enantiomers can be distinguished bymethods used to distinguish other chiral molecules with asymmetriccarbon atoms, such as optical rotation and circular dichroism. Theabsolute stereochemistry of chiral centers and enatiomers can bedetermined by x-ray crystallography.

Positional isomers and intermediates for their synthesis may be observedby characterization methods such as NMR and analytical HPLC. For certaincompounds where the energy barrier for interconversion is sufficientlyhigh, the E and Z isomers may be separated, for example by preparatoryHPLC.

Pharmaceutical Compositions and Administration

The compounds with which the invention is concerned are JAK kinaseinhibitors, such as JAK1 inhibitors, and are useful in the treatment ofseveral diseases, for example, inflammatory diseases, such as asthma.

Accordingly, another embodiment provides pharmaceutical compositions ormedicaments containing a compound of the invention or a pharmaceuticallyacceptable salt thereof, and a pharmaceutically acceptable carrier,diluent or excipient, as well as methods of using the compounds of theinvention to prepare such compositions and medicaments.

In one example, a compound of the invention or a pharmaceuticallyacceptable salt thereof may be formulated by mixing at ambienttemperature at the appropriate pH, and at the desired degree of purity,with physiologically acceptable carriers, i.e., carriers that arenon-toxic to recipients at the dosages and concentrations employed intoa galenical administration form. The pH of the formulation dependsmainly on the particular use and the concentration of compound, buttypically ranges anywhere from about 3 to about 8. In one example, acompound of the invention or a pharmaceutically acceptable salt thereofis formulated in an acetate buffer, at pH 5. In another embodiment, thecompounds of the present invention are sterile. The compound may bestored, for example, as a solid or amorphous composition, as alyophilized formulation or as an aqueous solution.

Compositions are formulated, dosed, and administered in a fashionconsistent with good medical practice. Factors for consideration in thiscontext include the particular disorder being treated, the particularmammal being treated, the clinical condition of the individual patient,the cause of the disorder, the site of delivery of the agent, the methodof administration, the scheduling of administration, and other factorsknown to medical practitioners.

It will be understood that the specific dose level for any particularpatient will depend upon a variety of factors including the activity ofthe specific compound employed, the age, body weight, general health,sex, diet, time of administration, route of administration, rate ofexcretion, drug combination and the severity of the particular diseaseundergoing treatment. Optimum dose levels and frequency of dosing willbe determined by clinical trial, as is required in the pharmaceuticalart. In general, the daily dose range for oral administration will liewithin the range of from about 0.001 mg to about 100 mg per kg bodyweight of a human, often 0.01 mg to about 50 mg per kg, for example 0.1to 10 mg per kg, in single or divided doses. In general, the daily doserange for inhaled administration will lie within the range of from about0.1 μg to about 1 mg per kg body weight of a human, preferably 0.1 μg to50 μg per kg, in single or divided doses. On the other hand, it may benecessary to use dosages outside these limits in some cases.

The compounds of the invention or a pharmaceutically acceptable saltthereof, may be administered by any suitable means, including oral,topical (including buccal and sublingual), rectal, vaginal, transdermal,parenteral, subcutaneous, intraperitoneal, intrapulmonary, intradermal,intrathecal, inhaled and epidural and intranasal, and, if desired forlocal treatment, intralesional administration. Parenteral infusionsinclude intramuscular, intravenous, intraarterial, intraperitoneal, orsubcutaneous administration. In some embodiments, inhaled administrationis employed.

The compounds of the present invention or a pharmaceutically acceptablesalt thereof, may be administered in any convenient administrative form,e.g., tablets, powders, capsules, lozenges, granules, solutions,dispersions, suspensions, syrups, sprays, vapors, suppositories, gels,emulsions, patches, etc. Such compositions may contain componentsconventional in pharmaceutical preparations, e.g., diluents (e.g.,glucose, lactose or mannitol), carriers, pH modifiers, buffers,sweeteners, bulking agents, stabilizing agents, surfactants, wettingagents, lubricating agents, emulsifiers, suspending agents,preservatives, antioxidants, opaquing agents, glidants, processing aids,colorants, perfuming agents, flavoring agents, other known additives aswell as further active agents.

Suitable carriers and excipients are well known to those skilled in theart and are described in detail in, e.g., Ansel, Howard C., et al.,Ansel's Pharmaceutical Dosage Forms and Drug Delivery Systems.Philadelphia: Lippincott, Williams & Wilkins, 2004; Gennaro, Alfonso R.,et al. Remington: The Science and Practice of Pharmacy. Philadelphia:Lippincott, Williams & Wilkins, 2000; and Rowe, Raymond C. Handbook ofPharmaceutical Excipients. Chicago, Pharmaceutical Press, 2005. Forexample, carriers include solvents, dispersion media, coatings,surfactants, antioxidants, preservatives (e.g., antibacterial agents,antifungal agents), isotonic agents, absorption delaying agents, salts,preservatives, drugs, drug stabilizers, gels, binders, excipients,disintegration agents, lubricants, sweetening agents, flavoring agents,dyes, such like materials and combinations thereof, as would be known toone of ordinary skill in the art (see, for example, Remington'sPharmaceutical Sciences, pp 1289-1329, 1990). Except insofar as anyconventional carrier is incompatible with the active ingredient, its usein the therapeutic or pharmaceutical compositions is contemplated.Exemplary excipients include dicalcium phosphate, mannitol, lactose,starch, magnesium stearate, sodium saccharine, cellulose, magnesiumcarbonate or combinations thereof. A pharmaceutical composition maycomprise different types of carriers or excipients depending on whetherit is to be administered in solid, liquid or aerosol form, and whetherit need to be sterile for such routes of administration.

For example, tablets and capsules for oral administration may be in unitdose presentation form, and may contain conventional excipients such asbinding agents, for example syrup, acacia, gelatin, sorbitol,tragacanth, or polyvinyl-pyrrolidone; fillers, for example, lactose,sugar, maize-starch, calcium phosphate, sorbitol or glycine; tablettinglubricant, for example, magnesium stearate, talc, polyethylene glycol orsilica; disintegrants, for example, potato starch, or acceptable wettingagents such as sodium lauryl sulfate. The tablets may be coatedaccording to methods well known in normal pharmaceutical practice. Oralliquid preparations may be in the form of, for example, aqueous or oilysuspensions, solutions, emulsions, syrups or elixirs, or may bepresented as a dry product for reconstitution with water or othersuitable vehicle before use. Such liquid preparations may containconventional additives such as suspending agents, for example, sorbitol,syrup, methyl cellulose, glucose syrup, gelatin hydrogenated ediblefats; emulsifying agents, for example, lecithin, sorbitan monooleate, oracacia; non-aqueous vehicles (which may include edible oils), forexample, almond oil, fractionated coconut oil, oily esters such asglycerine, propylene glycol, or ethyl alcohol; preservatives, forexample, methyl or propyl p-hydroxybenzoate or sorbic acid, and ifdesired conventional flavoring or coloring agents.

For topical application to the skin, a compound may be made up into acream, lotion or ointment. Cream or ointment formulations which may beused for the drug are conventional formulations well known in the art,for example as described in standard textbooks of pharmaceutics such asthe British Pharmacopoeia.

Compounds of the invention or a pharmaceutically acceptable salt thereofmay also be formulated for inhalation, for example, as a nasal spray, ordry powder or aerosol inhalers. For delivery by inhalation, the compoundis typically in the form of microparticles, which can be prepared by avariety of techniques, including spray-drying, freeze-drying andmicronisation. Aerosol generation can be carried out using, for example,pressure-driven jet atomizers or ultrasonic atomizers, such as by usingpropellant-driven metered aerosols or propellant-free administration ofmicronized compounds from, for example, inhalation capsules or other“dry powder” delivery systems.

By way of example, a composition of the invention may be prepared as asuspension for delivery from a nebulizer or as an aerosol in a liquidpropellant, for example, for use in a pressurized metered dose inhaler(PMDI). Propellants suitable for use in a PMDI are known to the skilledperson, and include CFC-12, HFA-134a, HFA-227, HCFC-22 (CCl₂F₂) andHFA-152 (CH₄F₂ and isobutane).

In some embodiments, a composition of the invention is in dry powderform, for delivery using a dry powder inhaler (DPI). Many types of DPIare known.

Microparticles for delivery by administration may be formulated withexcipients that aid delivery and release. For example, in a dry powderformulation, microparticles may be formulated with large carrierparticles that aid flow from the DPI into the lung. Suitable carrierparticles are known, and include lactose particles; they may have a massmedian aerodynamic diameter of, for example, greater than 90 μm.

In the case of an aerosol-based formulation, an example is:

Compound of the invention* 24 mg/canister

Lecithin, NF Liq. Conc. 1.2 mg/canister

Trichlorofluoromethane, NF 4.025 g/canister

Dichlorodifluoromethane, NF 12.15 g/canister.

* or a pharmaceutically acceptable salt thereof.

A compound of the invention or a pharmaceutically acceptable saltthereof may be dosed as described depending on the inhaler system used.In addition to the compound, the administration forms may additionallycontain excipients as described above, or, for example, propellants(e.g., Frigen in the case of metered aerosols), surface-activesubstances, emulsifiers, stabilizers, preservatives, flavorings, fillers(e.g., lactose in the case of powder inhalers) or, if appropriate,further active compounds.

For the purposes of inhalation, a large number of systems are availablewith which aerosols of optimum particle size can be generated andadministered, using an inhalation technique which is appropriate for thepatient. In addition to the use of adaptors (spacers, expanders) andpear-shaped containers (e.g., Nebulator®, Volumatic®), and automaticdevices emitting a puffer spray (Autohaler®), for metered aerosols, inthe case of powder inhalers in particular, a number of technicalsolutions are available (e.g., Diskhaler®, Rotadisk®, Turbohaler® or theinhalers, for example, as described in U.S. Pat. No. 5,263,475,incorporated herein by reference). Additionally, compounds of theinvention or a pharmaceutically acceptable salt thereof, may bedelivered in multi-chamber devices thus allowing for delivery ofcombination agents.

The compound or a pharmaceutically acceptable salt thereof, may also beadministered parenterally in a sterile medium. Depending on the vehicleand concentration used, the compound can either be suspended ordissolved in the vehicle. Advantageously, adjuvants such as a localanaesthetic, preservative or buffering agent can be dissolved in thevehicle.

Targeted Inhaled Drug Delivery

Compounds of the present invention may be intended for targeted inhaleddelivery. Optimisation of drugs for delivery to the lung by topical(inhaled) administration has been recently reviewed (Cooper, A. E. etal. Curr. Drug Metab. 2012, 13, 457-473).

Due to limitations in the delivery device, the dose of an inhaled drugis likely to be low (approximately <1 mg/day) in humans, whichnecessitates highly potent molecules. High potency against the target ofinterest is especially important for an inhaled drug due to factors suchas the limited amount of drug that can be delivered in a single pufffrom an inhaler, and the safety concerns related to a high aerosolburden in the lung (for example, cough or irritancy). For example, insome embodiments, a Ki of about 0.5 nM or less in a JAK1 biochemicalassay such as described herein, and an IC50 of about 20 nM or less in aJAK1 dependent cell based assay such as described herein, may bedesirable for an inhaled JAK1 inhibitor. In other embodiments, theprojected human dose of a compound of the present invention, or apharmaceutically acceptable salt thereof, is at least two times lessthan the projected human dose of a compound known in the art.Accordingly, in some embodiments, compounds (or a pharmaceuticallyacceptable salt thereof) described herein demonstrate such potencyvalues.

IL13 signaling is strongly implicated in asthma pathogenesis. IL13 is acytokine that requires active JAK1 in order to signal. Thus, inhibitionof JAK1 also inhibits IL13 signaling, which may provide benefit toasthma patients. Inhibition of IL13 signaling in an animal model (e.g.,a mouse model) may predict future benefit to human asthmatic patients.Thus, it may be beneficial for an inhaled JAK1 inhibitor to showsuppression of IL13 signaling in an animal model. Methods of measuringsuch suppression are known in the art. For example, as discussed hereinand is known in the art, JAK1-dependent STAT6 phosphorylation is knowndownstream of IL13 stimulation. Accordingly, in some embodiments,compounds (or a pharmaceutically acceptable salt thereof) describedherein demonstrate inhibition of lung pSTAT6 induction. To examinepharmacodynamic effects on pSTAT6 levels, compounds of the inventionwere co-dosed intra-nasally with 1 μg IL13 to female Balb/c mice.Compounds were formulated in 0.2% (v:v) Tween 80 in saline and mixed 1:1(v:v) with IL13 immediately prior to administration. The intranasaldoses were administered to lightly anaesthetised (isoflurane) mice bydispensing a fixed volume (50 μL) directly into the nostrils by pipetteto achieve the target dose level (3 mg/kg, 1 mg/kg, 0.3 mg/kg, 0.1mg/kg). At 0.25 hr post dose, blood samples (ca 0.5 mL) were collectedby cardiac puncture and plasma generated by centrifugation (1500 g, 10min, +4° C.). The lungs were perfused with chilled phosphate buffersaline (PBS), weighed and snap frozen in liquid nitrogen. All sampleswere stored at ca. −80° C. until analysis. Defrosted lung samples wereweighed and homogenised following the addition of 2 mL HPLC grade waterfor each gram of tissue, using an Omni-Prep Bead Ruptor at 4° C. Plasmaand lung samples were extracted by protein precipitation with threevolumes of acetonitrile containing Tolbutamide (50 ng/mL) and Labetalol(25 ng/mL) as analytical internal standards. Following vortex mixing andcentrifugation for 30 minutes at 3200 g and 4° C., the supernatants werediluted appropriately (e.g., 1:1 v:v) with HPLC grade water in a 96-wellplate. Representative aliquots of plasma and lung samples were assayedfor the parent compound by LC-MS/MS, against a series of matrix matchedcalibration and quality control standards. The standards were preparedby spiking aliquots of control Balb/c mouse plasma or lung homogenate(2:1 in HPLC grade water) with test compound and extracting as describedfor the experimental samples. A lung:plasma ratio was determined as theratio of the mean lung concentration (04) to the mean plasmaconcentration (04) at the sampling time (0.25 h). Theoretical targetengagement was calculated with the following equation, assuming that alldrug was within lung tissue and the fraction unbound was available tointeract with the target:

(unbound tissue concentration/(unbound tissue concentration+in vitrocellular potency i.e., IC50))*100

To measure pSTAT6 levels, mouse lungs were stored frozen at −80° C.until assay and homogenised in 0.6 ml ice-cold cell lysis buffer (CellSignalling Technologies, catalogue #9803S) supplemented with 1 mM PMSFand a cocktail of protease (Sigma Aldrich, catalogue # P8340) andphosphatase (Sigma Aldrich, catalogue # P5726 and P0044) inhibitors.Samples were centrifuged at 16060×g for 4 minutes at 4° C. to removetissue debris and protein concentration of homogenates determined usingthe Pierce BCA protein assay kit (catalogue #23225). Samples werediluted to a protein concentration of 5 mg/ml in ice-cold distilledwater and assayed for pSTAT6 levels by Meso Scale Discoveryelectro-chemiluminescent immuno-assay. Briefly, 5 μl/well 150 μg/mlSTAT6 capture antibody (R&D Systems, catalogue # MAB 2169) was coatedonto 96 well Meso Scale Discovery High Binding Plates (catalogue #L15XB-3) and air-dried for 5 hours at room temperature. Plates wereblocked by addition of 1500/well 30 mg/ml Meso Scale Discovery Blocker A(catalogue # R93BA-4) and incubation for 2 hours at room temperature ona microplate shaker. Blocked plates were washed 4 times with Meso ScaleDiscovery TRIS wash buffer (catalogue # R61TX-1), followed by transferof 50 μl/well lung homogenate to achieve a protein loading of 250μg/well. Assay plates were incubated overnight at 4° C. and washed 4times with TRIS wash buffer before addition of 25 μl/well 2.5 μg/mlsulfotag-labelled pSTAT6 detection antibody (BD Pharmingen, catalogue#558241) for 2 hours at room temperature on a microplate shaker. Plateswere washed 4 times with TRIS wash buffer and 150 μl/well 1X Meso ScaleDiscovery Read Buffer T (catalogue # R92TC-1) added. Lung homogenatepSTAT6 levels were quantified by detection of electro-chemiluminescenceon a Meso Scale Discovery SECTOR S 600 instrument.

Selectivity between JAK1 and JAK2 may be important for an inhaled JAK1inhibitor. For example, GMCSF (granulocyte-macrophage colony-stimulatingfactor) is a cytokine that signals through JAK2 exclusively.Neutralization of GMCSF activity is associated with pulmonary alveolarproteinosis (PAP) in the lung. However, submaximal JAK2 suppression doesnot appear to be associated with PAP. Thus, even modest JAK1 vs JAK2selectivity may be of benefit in avoiding full suppression of the GMCSFpathway and avoiding PAP. For example, compounds with about 2×-5×selectivity for JAK1 over JAK2 may be of benefit for an inhaled JAK1inhibitor. Accordingly, in some embodiments, compounds (or apharmaceutically acceptable salt thereof) described herein demonstratesuch selectivity. Methods of measuring JAK1 and JAK2 selectivity areknown in the art, and information can also be found in the Examplesherein.

Additionally, it may be desirable for an inhaled JAK1 inhibitor to beselective over one or more other kinases to reduce the likelihood ofpotential toxicity due to off-target kinase pathway suppression. Thus,it may also be of benefit for an inhaled JAK1 inhibitor to be selectiveagainst a broad panel of non-JAK kinases, such as in protocols availablefrom ThermoFisher Scientific's SelectScreen™ Biochemical KinaseProfiling Service using Adapta™ Screening Protocol Assay Conditions(Revised Jul. 29, 2016), LanthaScreen™ Eu Kinase Binding Assay ScreeningProtocol and Assay Conditions (Revised Jun. 7, 2016), and/or Z'LYTE™Screening Protocol and Assay Conditions (Revised Sep. 16, 2016). Forexample, a compound of the present invention, or a pharmaceuticallyacceptable salt thereof, exhibits at least 50-fold selectivity for JAK1versus a panel of non-JAK kinases. Accordingly, in some embodiments,compounds (or a pharmaceutically acceptable salt thereof) describedherein demonstrate such selectivity.

Hepatocyte toxicity, general cytotoxicity or cytotoxicity of unknownmechanism is an undesirable feature for a potential drug, includinginhaled drugs. It may be of benefit for an inhaled JAK1 inhibitor tohave low intrinsic cytotoxicity against various cell types. Typical celltypes used to assess cytotoxicity include both primary cells such ashuman hepatocytes, and proliferating established cell lines such asJurkat, HEK-293, and H23. For example, it may be of benefit for aninhaled JAK1 inhibitor to have an IC₅₀ of greater than 50 μM or greaterthan 100 μM in cytotoxicity measurements against such cell types.Accordingly, in some embodiments, compounds (or a pharmaceuticallyacceptable salt thereof) described herein demonstrate such values.Methods of measuring cytotoxicity are known in the art. In someembodiments, compounds described herein were tested as follows:

(a) Jurkat, H23, and HEK293T cells were maintained at a sub confluentdensity in T175 flasks. Cells were plated at 450 cells/45 μl medium inGreiner 384 well black/clear tissue culture treated plates. (GreinerCatalog #781091). After dispensing cells, plates were equilibrated atroom temperature for 30 minutes. After 30 minutes at room temperature,cells were incubated overnight at 37° C. in a CO₂ and humiditycontrolled incubator. The following day, cells were treated withcompounds diluted in 100% DMSO (final DMSO concentration on cells=0.5%)with a 10 point dose-response curve with a top concentration of 50 μM.Cells and compounds were then incubated for 72 hours overnight at 37° C.in a CO₂ and humidity controlled incubator. After 72 hours ofincubation, viability was measured using CellTiterGlo® (Promega Catalog#G7572) to all wells. After incubation at room temperature for 20minutes, plates were read on EnVision™ (Perkin Elmer Life Sciences)using luminescence mode;

(b) using human primary hepatocytes: the test compound was prepared as a10 mM solution in DMSO. Additionally, a positive control such asChlorpromazine was prepared as a 10 mM solution in DMSO. Test compoundswere typically assessed using a 7-point dose response curve with 2-folddilutions. Typically, the maximum concentration tested was 50-100 μM.The top concentration was typically dictated by solubility of the testcompound. Cryopreserved primary human hepatocytes(BioreclamationIVT)(lot IZT) were thawed in InVitroGro™ HT thawing media(BioreclamationIVT) at 37° C., pelleted and resuspended. Hepatocyteviability was assessed by Trypan blue exclusion and cells were plated inblack-walled, BioCoat™ collagen 384-well plates (Corning BD) at adensity of 13,000 cells/well in InVitroGro™ CP plating mediasupplemented with 1% Torpedo™ Antibiotic Mix (BioreclamationIVT) and 5%fetal bovine serum. Cells were incubated overnight for 18 hours (37° C.,5% CO₂) prior to treatment. Following 18 hours incubation, plating mediawas removed and hepatocytes were treated with compounds diluted inInVitroGro™ HI incubation media containing 1% Torpedo™ Antibiotic Mixand 1% DMSO (serum-free conditions). Hepatocytes were treated with testcompounds at concentrations such as 0.78, 1.56, 3.12, 6.25, 12.5, 25,and 50 μM at a final volume of 50 μL. A positive control (e.g.,Chlorpromazine) was included in the assay, typically at the sameconcentrations as the test compound. Additional cells were treated with1% DMSO as a vehicle control. All treatments were for a 48 hour timeperiod (at 37° C., 5% CO₂) and each treatment condition was performed intriplicate. Following 48 hours of compound treatment, CellTiter-Glo®cell viability assay (Promega) was used as the endpoint assay to measureATP content as a determination of cell viability. The assay wasperformed according to manufacture instructions. Luminescence wasdetermined on an EnVision™ Muliplate Reader (PerkinElmer, Waltham,Mass., USA). Luminescence data was normalized to vehicle (1% DMSO)control wells. Inhibition curves and IC₅₀ estimates were generated bynon-linear regression of log-transformed inhibitor concentrations(7-point serial dilutions including vehicle) vs. normalized responsewith variable Hill slopes, with top and bottom constrained to constantvalues of 100 and 0, respectively (GraphPad Prism™, GraphPad Software,La Jolla, Calif., USA).

Inhibition of the hERG (human ether-à-go-go-related gene) potassiumchannel may lead to long QT syndrome and cardiac arrhythmias. Althoughplasma levels of an inhaled JAK1 inhibitor are expected to be low,lung-deposited compound exiting the lung via pulmonary absorption intothe bloodstream will circulate directly to the heart. Thus, local heartconcentrations of an inhaled JAK1 inhibitor may be transiently higherthan total plasma levels, particularly immediately after dosing. Thus,it may be of benefit to minimize hERG inhibition of an inhaled JAK1inhibitor. For example, in some embodiments, a hERG IC50 greater than30× over the free-drug plasma Cmax is preferred. Accordingly, in someembodiments, compounds (or a pharmaceutically acceptable salt thereof)of the invention demonstrate minimized hERG inhibition under conditionssuch as:

(a) using hERG 2pt automatic patch clamp conditions to examine in vitroeffects of a compound on hERG expressed in mammalizan cells, evaluatedat room temperature using the QPatch HT® (Sophion Bioscience A/S,Denmark), an automatic parallel patch clamp system. In some cases,compounds were tested at only one or two concentrations such as 1 or 10uM. In other cases a more extensive concentration response relationshipwas established to allow estimation of IC50. For example, test compoundconcentrations were selected to span the range of approximately 10-90%inhibition in half-log increments. Each test article concentration wastested in two or more cells (n≥2). The duration of exposure to each testarticle concentration was a minimum of 3 minutes; and/or

(b) those described in WO 2014/074775, in the Examples, under “Effect onCloned hERG Potassium Channels Expressed in Mammalian Cells,” aChanTest™, a Charles River Company, protocol with the following changes:cells stably expressing hERG were held at −80 mV. Onset and steady stateinhibition of hERG potassium current due to compound were measured usinga pulse pattern with fixed amplitudes (conditioning prepulse: +20 mV for1 s; repolarizing test ramepto −90 mV (−0.5 V/s) repeated at 5 sintervals). Each recording ended with a final application of asupramaximal concentration of a reference substance, E-4021 (500 nM)(Charles River Company). The remaining uninhibited current wassubtracted off-line digitially from the data to determine the potency ofthe test substance for hERG inhibition.

CYP (cytochrome P450) inhibition may not be a desirable feature for aninhaled JAK1 inhibitor. For example, a reversible or time dependent CYPinhibitor may cause an undesired increase in its own plasma levels, orin the plasma levels of other co-administered drugs (drug-druginteractions). Additionally, time dependent CYP inhibition is sometimescaused by biotransformation of parent drug to a reactive metabolite.Such reactive metabolites may covalently modify proteins, potentiallyleading to toxicity. Thus, minimizing reversible and time dependent CYPinhibition may be of benefit to an inhaled JAK1 inhibitor. Accordingly,in some embodiments, compounds (or a pharmaceutically acceptable saltthereof) of the present invention demonstrate minimal or no reversibleand/or time dependent CYP inhibition. Methods of measuring CYPinhibition are known in the art. CYP inhibition of compounds describedherein were assessed over a concentration range of 0.16-10 uM ofcompound using pooled (n=150) human liver microsomes (Corning,Tewksbury, Mass.) using methods previously reported (Halladay et al.,Drug Metab. Lett. 2011, 5, 220-230). Incubation duration and proteinconcentration was dependent on the CYP isoform and the probesubstrate/metabolites assessed. The following substrate/metabolites, andincubation times and protein concentrations for each CYP were used:CYP1A2, phenacetin/acetaminophen, 30 min, 0.03 mg/ml protein; CYP2C9,warfarin/7-hydroxywarfarin, 30 min, 0.2 mg/ml protein; CYP2C19,mephenytoin/4-hydroxymephenytoin, 40 min, 0.2 mg/ml protein; CYP2D6,dextromethorphan/dextrorphan, 10 min, 0.03 mg/ml protein; CYP3A4,midazolam/1-hydroxymidazolam, 10 min, 0.03 mg/ml protein and CYP3A4testosterone/6β-hydroxytestosterone, 10 min, 0.06 mg/ml protein. Theseconditions were previously determined to be in the linear rate offormation for the CYP-specific metabolites. All reaction were initiatedwith 1 mM NADPH and terminated by the addition of 0.1% formic acid inacetonitrile containing appropriate stable labeled internal standard.Samples were analyzed by LC-MS/MS.

For compounds destined to be delivered via dry powder inhalation thereis also a requirement to be able to generate crystalline forms of thecompound that can be micronized to 1-5 μm in size. Particle size is animportant determinant of lung deposition of an inhaled compound.Particles with a diameter of less than 5 microns (μm) are typicallydefined as respirable. Particles with a diameter larger than 5 μm aremore likely to deposit in the oropharynx and are correspondingly lesslikely to be deposited in the lung. Additionally, fine particles with adiameter of less than 1 μm are more likely than larger particles toremain suspended in air, and are correspondingly more likely to beexhaled from the lung. Thus, a particle diameter of 1-5 μm may be ofbenefit for an inhaled medication whose site of action is in the lung.Typical methods used to measure particle size include laser diffractionand cascade impaction. Typical values used to define particle sizeinclude:

-   -   D10, D50, and D90. These are measurements of particle diameter        that indicate, respectively, 10%, 50%, or 90% of the sample is        below that value. For example a D50 of 3 μm indicates that 50%        of the sample is below 3 μm in size.    -   Mass mean aerodynamic diameter (MMAD). MMAD is the diameter at        which 50% of the particles by mass are larger and 50% are        smaller. MMAD is a measure of central tendency.    -   Geometric Standard Deviation (GSD). GSD is a measure of the        magnitude in dispersity from the MMAD, or the spread in        aerodynamic particle size distribution.        A common formulation for inhaled medications is a dry powder        preparation including the active pharmaceutical ingredient (API)        blended with a carrier such as lactose with or without        additional additives such as magnesium stearate. For this        formulation and others, it may be beneficial for the API itself        to possess properties that allow it to be milled to a respirable        particle size of 1-5 μm. Agglomeration of particles is to be        avoided, which can be measured by methods known in the art, such        as examining D90 values under different pressure conditions.        Accordingly, in some embodiments, compounds (or a        pharmaceutically acceptable salt thereof) of the present        invention can be prepared with such a respirable particle size        with little or no agglomeration.

As for crystallinity, for some formulations of inhaled drugs, includinglactose blends, it is important that API of a specific crystalline formis used. Crystallinity and crystalline form may impact many parametersrelevant to an inhaled drug including but not limited to: chemical andaerodynamic stability over time, compatibility with inhaled formulationcomponents such as lactose, hygroscopicity, lung retention, and lungirritancy. Thus, a stable, reproducible crystalline form may be ofbenefit for an inhaled drug. Additionally, the techniques used to millcompounds to the desired particle size are often energetic and may causelow melting crystalline forms to convert to other crystalline forms, orto become fully or partially amorphous. A crystalline form with amelting point of less than 150° C. may be incompatible with milling,while a crystalline form with a melting point of less than 100° C. islikely to be non-compatible with milling. Thus, it may be beneficial foran inhaled medication to have a melting point of at least greater than100° C., and ideally greater than 150° C. Accordingly, in someembodiments, compounds (or a pharmaceutically acceptable salt thereof)described herein demonstrate such properties.

Additionally, minimizing molecular weight may help to lower theefficacious dose of an inhaled JAK1 inhibitor. Lower molecular weightresults in a corresponding higher number of molecules per unit mass ofthe active pharmaceutical ingredient (API). Thus, it may be of benefitto find the smallest molecular weight inhaled JAK1 inhibitor thatretains all the other desired properties of an inhaled drug.

Finally, the compound needs to maintain a sufficient concentration inthe lung over a given time period so as to be able to exert apharmacological effect of the desired duration, and for pharmacologicaltargets where systemic inhibition of said target is undesired, to have alow systemic exposure. The lung has an inherently high permeability toboth large molecules (proteins, peptides) as well as small moleculeswith concomitant short lung half-lives, thus it may be necessary toattenuate the lung absorption rate through modification of one or morefeatures of the compounds: minimizing membrane permeability, increasingpKa, increasing cLogP, decreasing solubility, reducing dissolution rate,or introducing a degree of basicity (e.g., introducing an amine) intothe compound to enhance binding to the phospholipid-rich lung tissue orthrough trapping in acidic sub-cellular compartments such as lysosomes(pH 5). Methods of measuring such properties are known in the art.

Accordingly, in some embodiments, a compound of the present invention(or a pharmaceutically acceptable salt thereof) exhibits one or more ofthe above features. Further, in some embodiments, a compound of thepresent invention favorably exhibits one or more of these featuresrelative to a compound known in the art—this may be particularly truefor compounds of the art intended as oral drugs versus inhaled. Forexample, compounds with rapid oral absorption are typically poorlyretained in the lung on inhalation.

Methods of Treatment with and Uses of Janus Kinase Inhibitors

The compounds of the present invention or a pharmaceutically acceptablesalt thereof, inhibit the activity of a Janus kinase, such as JAK1kinase. For example, a compound or a pharmaceutically acceptable saltthereof inhibits the phosphorylation of signal transducers andactivators of transcription (STATs) by JAK1 kinase as well as STATmediated cytokine production. Compounds of the present invention areuseful for inhibiting JAK1 kinase activity in cells through cytokinepathways, such as IL-6, IL-15, IL-7, IL-2, IL-4, IL-9, IL-10, IL-13,IL-21, G-CSF, IFNalpha, IFNbeta or IFNgamma pathways. Accordingly, inone embodiment is provided a method of contacting a cell with a compoundof the present invention or a pharmaceutically acceptable salt thereof,to inhibit a Janus kinase activity in the cell (e.g., JAK1 activity).

The compounds can be used for the treatment of immunological disordersdriven by aberrant IL-6, IL-15, IL-7, IL-2, IL-4, IL9, IL-10, IL-13,IL-21, G-CSF, IFNalpha, IFNbeta or IFNgamma cytokine signaling.

Accordingly, one embodiment includes a compound of the present inventionor a pharmaceutically acceptable salt thereof, for use in therapy.

In some embodiments, there is provided use of a compound of the presentinvention or a pharmaceutically acceptable salt thereof, in thetreatment of an inflammatory disease. Further provided is use of acompound of the present invention or a pharmaceutically acceptable saltthereof for the preparation of a medicament for the treatment of aninflammatory disease, such as asthma. Also provided is a compound of thepresent invention or a pharmaceutically acceptable salt thereof for usein the treatment of an inflammatory disease, such as asthma.

Another embodiment includes a method of preventing, treating orlessening the severity of a disease or condition, such as asthma,responsive to the inhibition of a Janus kinase activity, such as JAK1kinase activity, in a patient. The method can include the step ofadministering to a patient a therapeutically effective amount of acompound of the present invention or a pharmaceutically acceptable saltthereof. In one embodiment, the disease or condition responsive to theinhibition of a Janus kinase, such as JAK1 kinase, is asthma.

In one embodiment, the disease or condition is cancer, stroke, diabetes,hepatomegaly, cardiovascular disease, multiple sclerosis, Alzheimer'sdisease, cystic fibrosis, viral disease, autoimmune diseases,atherosclerosis, restenosis, psoriasis, rheumatoid arthritis,inflammatory bowel disease, asthma, allergic disorders, inflammation,neurological disorders, a hormone-related disease, conditions associatedwith organ transplantation (e.g., transplant rejection),immunodeficiency disorders, destructive bone disorders, proliferativedisorders, infectious diseases, conditions associated with cell death,thrombin-induced platelet aggregation, liver disease, pathologic immuneconditions involving T cell activation, CNS disorders or amyeloproliferative disorder.

In one embodiment, the inflammatory disease is rheumatoid arthritis,psoriasis, asthma, inflammatory bowel disease, contact dermatitis ordelayed hypersensitivity reactions. In one embodiment, the autoimmunedisease is rheumatoid arthritis, lupus or multiple sclerosis.

In another embodiment, a compound of the present invention or apharmaceutically acceptable salt thereof may be used to treat lungdiseases such as a fibrotic lung disease or an interstitial lung disease(e.g., an interstitial pneumonia). In some embodiments, a compound ofthe present invention or a pharmaceutically acceptable salt thereof maybe used to treat idiopathic pulmonary fibrosis (IPF), systemic sclerosisinterstitial lung disease (SSc-ILD)), nonspecific interstitial pneumonia(NSIP), rheumatoid arthritis-associated interstitial lung disease(RA-ILD), sarcoidosis, hypersensitivity pneumonitis, or ILD secondary toconnective tissue disease beyond scleroderma (e.g., polymyositis,dermatomyositis, rheumatoid arthritis, systemic lupus erythematosus(SLE), or mixed connective tissue disease).

In one embodiment, the cancer is breast, ovary, cervix, prostate,testis, penile, genitourinary tract, seminoma, esophagus, larynx,gastric, stomach, gastrointestinal, skin, keratoacanthoma, follicularcarcinoma, melanoma, lung, small cell lung carcinoma, non-small celllung carcinoma (NSCLC), lung adenocarcinoma, squamous carcinoma of thelung, colon, pancreas, thyroid, papillary, bladder, liver, biliarypassage, kidney, bone, myeloid disorders, lymphoid disorders, hairycells, buccal cavity and pharynx (oral), lip, tongue, mouth, salivarygland, pharynx, small intestine, colon, rectum, anal, renal, prostate,vulval, thyroid, large intestine, endometrial, uterine, brain, centralnervous system, cancer of the peritoneum, hepatocellular cancer, headcancer, neck cancer, Hodgkin's or leukemia.

In one embodiment, the disease is a myeloproliferative disorder. In oneembodiment, the myeloproliferative disorder is polycythemia vera,essential thrombocytosis, myelofibrosis or chronic myelogenous leukemia(CML).

Another embodiment includes the use of a compound of the presentinvention or a pharmaceutically acceptable salt thereof, for themanufacture of a medicament for the treatment of a disease describedherein (e.g., an inflammatory disorder, an immunological disorder orcancer). In one embodiment, the invention provides a method of treatinga disease or condition as described herein e.g., an inflammatorydisorder, an immunological disorder or cancer) by targeting inhibitionof a JAK kinase, such as JAK1.

Combination Therapy

The compounds may be employed alone or in combination with other agentsfor treatment. The second or further (e.g., third) compound of apharmaceutical composition or dosing regimen typically has complementaryactivities to the compound of this invention such that they do notadversely affect each other. Such agents are suitably present incombination in amounts that are effective for the purpose intended. Thecompounds may be administered together in a unitary pharmaceuticalcomposition or separately and, when administered separately this mayoccur simultaneously or sequentially. Such sequential administration maybe close or remote in time.

For example, other compounds may be combined with a compound of thepresent invention or a pharmaceutically acceptable salt thereof for theprevention or treatment of inflammatory diseases, such as asthma.Suitable therapeutic agents for a combination therapy include, but arenot limited to: an adenosine A2A receptor antagonist; an anti-infective;a non-steroidal Glucocorticoid Receptor (GR Receptor) agonist; anantioxidant; a (32 adrenoceptor agonist; a CCR1 antagonist; a chemokineantagonist (not CCR1); a corticosteroid; a CRTh2 antagonist; a DP1antagonist; a formyl peptide receptor antagonist; a histone deacetylaseactivator; a chloride channel hCLCA1 blocker; an epithelial sodiumchannel blocker (ENAC blocker; an inter-cellular adhesion molecule 1blocker (ICAM blocker); an IKK2 inhibitor; a JNK inhibitor; a transientreceptor potential ankyrin 1 (TRPA1) inhibitor; a Bruton's tyrosinekinase (BTK) inhibitor (e.g., fenebrutinib); a spleen tyrosine kinase(SYK) inhibitor; a tryptase-beta antibody; an ST2 receptor antibody(e.g., AMG 282); a cyclooxygenase inhibitor (COX inhibitor); alipoxygenase inhibitor; a leukotriene receptor antagonist; a dual β2adrenoceptor agonist/M3 receptor antagonist (MABA compound); a MEK-1inhibitor; a myeloperoxidase inhibitor (MPO inhibitor); a muscarinicantagonist; a p38 MAPK inhibitor; a phosphodiesterase PDE4 inhibitor; aphosphatidylinositol 3-kinase δ inhibitor (PI3-kinase δ inhibitor); aphosphatidylinositol 3-kinase γ inhibitor (PI3-kinase γ inhibitor); aperoxisome proliferator activated receptor agonist (PPARγ agonist); aprotease inhibitor; a retinoic acid receptor modulator (RAR γmodulator); a statin; a thromboxane antagonist; a TLR7 receptor agonist;or a vasodilator.

In addition, a compound of the present invention or a pharmaceuticallyacceptable salt thereof, may be combined with: (1) corticosteroids, suchas alclometasone dipropionate, amelometasone, beclomethasonedipropionate, budesonide, butixocort propionate, biclesonide, clobetasolpropionate, desisobutyrylciclesonide, dexamethasone, etiprednoldicloacetate, fluocinolone acetonide, fluticasone furoate, fluticasonepropionate, loteprednol etabonate (topical) or mometasone furoate; (2)β2-adrenoreceptor agonists such as salbutamol, albuterol, terbutaline,fenoterol, bitolterol, carbuterol, clenbuterol, pirbuterol, rimoterol,terbutaline, tretoquinol, tulobuterol and long acting β2-adrenoreceptoragonists such as metaproterenol, isoproterenol, isoprenaline,salmeterol, indacaterol, formoterol (including formoterol fumarate),arformoterol, carmoterol, abediterol, vilanterol trifenate, orolodaterol; (3) corticosteroid/long acting (32 agonist combinationproducts such as salmeterol/fluticasone propionate (Advair®, also soldas Seretide®), formoterol/budesonide (Symbicort®),formoterol/fluticasone propionate (Flutiform®), formoterol/ciclesonide,formoterol/mometasone furoate, indacaterol/mometasone furoate,vilanterol trifenate/fluticasone furoate (BREO ELLIPTA), orarformoterol/ciclesonide; (4) anticholinergic agents, for example,muscarinic-3 (M3) receptor antagonists such as ipratropium bromide,tiotropium bromide, aclidinium bromide (LAS-34273), glycopyrroniumbromide, or umeclidinium bromide; (5)M3-anticholinergic/β2-adrenoreceptor agonist combination products suchas vilanterol/umeclidinium (Anoro® Ellipta®), olodaterol/tiotropiumbromide, glycopyrronium bromide/indacaterol (Ultibro®, also sold asXoterna®), fenoterol hydrobromide/ipratropium bromide (Berodual®),albuterol sulfate/ipratropium bromide (Combivent®), formoterolfumarate/glycopyrrolate, or aclidinium bromide/formoterol; (6) dualpharmacology M3-anticholinergic/β2-adrenoreceptor agonists such asbatefenterol succinate, AZD-2115 or LAS-190792; (7) leukotrienemodulators, for example, leukotriene antagonists such as montelukast,zafirulast or pranlukast or leukotriene biosynthesis inhibitors such aszileuton, or LTB4 antagonists such as amelubant, or FLAP inhibitors suchas fiboflapon, GSK-2190915; (8) phosphodiesterase-IV (PDE-IV) inhibitors(oral or inhaled), such as roflumilast, cilomilast, oglemilast,rolipram, tetomilast, AVE-8112, revamilast, CHF 6001; (9)antihistamines, for example, selective histamine-1 (H1) receptorantagonists such as fexofenadine, citirizine, loratidine or astemizoleor dual H1/H3 receptor antagonists such as GSK 835726, or GSK 1004723;(10) antitussive agents, such as codeine or dextramorphan; (11) amucolytic, for example, N-acetyl cysteine or fudostein; (12) aexpectorant/mucokinetic modulator, for example, ambroxol, hypertonicsolutions (e.g., saline or mannitol) or surfactant; (13) a peptidemucolytic, for example, recombinant human deoxyribonoclease I(dornase-alpha and rhDNase) or helicidin; (14) antibiotics, for exampleazithromycin, tobramycin or aztreonam; (15) non-selective COX-1/COX-2inhibitors, such as ibuprofen or ketoprofen; (16) COX-2 inhibitors, suchas celecoxib and rofecoxib; (17) VLA-4 antagonists, such as thosedescribed in WO 97/03094 and WO 97/02289, each incorporated herein byreference; (18) TACE inhibitors and TNF-α inhibitors, for exampleanti-TNF monoclonal antibodies, such as Remicade® and CDP-870 and TNFreceptor immunoglobulin molecules, such as Enbrel®; (19) inhibitors ofmatrix metalloprotease, for example MMP-12; (20) human neutrophilelastase inhibitors, such as BAY-85-8501 or those described in WO2005/026124, WO 2003/053930 and WO 2006/082412, each incorporated hereinby reference; (21) A2b antagonists such as those described in WO2002/42298, incorporated herein by reference; (22) modulators ofchemokine receptor function, for example antagonists of CCR3 and CCR8;(23) compounds which modulate the action of other prostanoid receptors,for example, a thromboxane A2 antagonist; DP1 antagonists such aslaropiprant or asapiprant CRTH2 antagonists such as OC000459,fevipiprant, ADC 3680 or ARRY 502; (24) PPAR agonists including PPARalpha agonists (such as fenofibrate), PPAR delta agonists, PPAR gammaagonists such as pioglitazone, rosiglitazone and balaglitazone; (25)methylxanthines such as theophylline or aminophylline andmethylxanthine/corticosteroid combinations such astheophylline/budesonide, theophylline/fluticasone propionate,theophylline/ciclesonide, theophylline/mometasone furoate andtheophylline/beclometasone dipropionate; (26) A2a agonists such as thosedescribed in EP1052264 and EP1241176; (27) CXCR2 or IL-8 antagonistssuch as AZD-5069, AZD-4721, or danirixin; (28) IL-R signallingmodulators such as kineret and ACZ 885; (29) MCP-1 antagonists such asABN-912; (30) a p38 MAPK inhibitor such as BCT197, JNJ49095397,losmapimod or PH-797804; (31) TLR7 receptor agonists such as AZD 8848;(32) PI3-kinase inhibitors such as RV1729 or GSK2269557 (nemiralisib);(33) triple combination products such as TRELEGY ELLIPTA (fluticasonefuroate, umeclidinium bromide, and vilanterol); or (34) small moleculeinhibitors of TRPA1, BTK, or SYK.

In some embodiments a compound of the present invention or apharmaceutically acceptable salt thereof, can be used in combinationwith one or more additional drugs, for example anti-hyperproliferative,anti-cancer, cytostatic, cytotoxic, anti-inflammatory orchemotherapeutic agents, such as those agents disclosed in U.S. Publ.Appl. No. 2010/0048557, incorporated herein by reference. A compound ofthe present invention or a pharmaceutically acceptable salt thereof, canbe also used in combination with radiation therapy or surgery, as isknown in the art.

Combinations of any of the foregoing with a compound of the presentinvention or a pharmaceutically acceptable salt thereof are specificallycontemplated.

Articles of Manufacture

Another embodiment includes an article of manufacture (e.g., a kit) fortreating a disease or disorder responsive to the inhibition of a Januskinase, such as a JAK1 kinase. The kit can comprise:

(a) a first pharmaceutical composition comprising a compound of thepresent invention or a pharmaceutically acceptable salt thereof; and

(b) instructions for use.

In another embodiment, the kit further comprises:

(c) a second pharmaceutical composition, such as a pharmaceuticalcomposition comprising an agent for treatment as described above, suchas an agent for treatment of an inflammatory disorder, or achemotherapeutic agent.

In one embodiment, the instructions describe the simultaneous,sequential or separate administration of said first and secondpharmaceutical compositions to a patient in need thereof.

In one embodiment, the first and second compositions are contained inseparate containers. In another embodiment, the first and secondcompositions are contained in the same container.

Containers for use include, for example, bottles, vials, syringes,blister pack, etc. The containers may be formed from a variety ofmaterials such as glass or plastic. The container includes a compound ofthe present invention or a pharmaceutically acceptable salt thereof,which is effective for treating the condition and may have a sterileaccess port (for example the container may be an intravenous solutionbag or a vial having a stopper pierceable by a hypodermic injectionneedle). The label or package insert indicates that the compound is usedfor treating the condition of choice, such as asthma or cancer. In oneembodiment, the label or package inserts indicates that the compound canbe used to treat a disorder. In addition, the label or package insertmay indicate that the patient to be treated is one having a disordercharacterized by overactive or irregular Janus kinase activity, such asoveractive or irregular JAK1 activity. The label or package insert mayalso indicate that the compound can be used to treat other disorders.

Alternatively, or additionally, the kit may further comprise a second(or third) container comprising a pharmaceutically acceptable buffer,such as bacteriostatic water for injection (BWFI), phosphate-bufferedsaline, Ringer's solution or dextrose solution. It may further includeother materials desirable from a commercial and user standpoint,including other buffers, diluents, filters, needles, and syringes.

In order to illustrate the invention, the following examples areincluded. However, it is to be understood that these examples do notlimit the invention and are only meant to suggest a method of practicingthe invention. Persons skilled in the art will recognize that thechemical reactions described may be readily adapted to prepare othercompounds of the present invention, and alternative methods forpreparing the compounds are within the scope of this invention. Forexample, the synthesis of non-exemplified compounds according to theinvention may be successfully performed by modifications apparent tothose skilled in the art, e.g., by appropriately protecting interferinggroups, by utilizing other suitable reagents known in the art other thanthose described, or by making routine modifications of reactionconditions. Alternatively, other reactions disclosed herein or known inthe art will be recognized as having applicability for preparing othercompounds of the invention.

EXAMPLES General Experimental Details

All solvents and commercial reagents were used as received unlessotherwise stated. Where products were purified by chromatography onsilica this was carried out using either a glass column manually packedwith silica gel (Kieselgel 60, 220-440 mesh, 35-75 μm) or an Isolute®SPE Si II cartridge. ‘Isolute SPE Si cartridge’ refers to a pre-packedpolypropylene column containing unbonded activated silica with irregularparticles with average size of 50 μm and nominal 60 Å porosity. Where anIsolute® SCX-2 cartridge was used, ‘Isolute® SCX-2 cartridge’ refers toa pre-packed polypropylene column containing a non-end-cappedpropylsulphonic acid functionalised silica strong cation exchangesorbent.

LCMS Conditions Method A

Experiments were performed on a SHIMADZU LCMS-2020 with aC18-reverse-phase column (50×3 mm Shim-Pack XR-ODS, 2.2 μm particlesize), elution with solvent A: water+0.05% trifluoroacetic acid; solventB: acetonitrile+0.05% trifluoroacetic acid. Gradient:

Gradient-Time flow ml/min % A % B 0.00 1.2 95 5 2.00 1.2 5 95 2.70 1.2 595 2.75 1.2 95 5

Detection—UV (220 and 254 nm) and ELSD Method B

Experiments were performed on a SHIMADZU LCMS-2020 with aC18-reverse-phase column (50×3 mm Shim-Pack XR-ODS, 2.2 μm particlesize), elution with solvent A: water+0.05% trifluoroacetic acid; solventB: acetonitrile+0.05% trifluoroacetic acid. Gradient:

Gradient-Time flow ml/min % A % B 0.00 1.2 80 20 3.60 1.2 40 60 4.00 1.20 100 4.70 1.2 0 100 4.75 1.2 95 5

Detection—UV (220 and 254 nm) and ELSD Method C

Experiments were performed on a SHIMADZU LCMS-2020 with aC18-reverse-phase column (50×3 mm Shim-Pack XR-ODS, 2.2 μm particlesize), elution with solvent A: water+0.05% trifluoroacetic acid; solventB: acetonitrile+0.05% trifluoroacetic acid. Gradient:

Gradient-Time flow ml/min % A % B 0.00 1.2 95 5 3.00 1.2 5 95 3.70 1.2 595 3.75 1.2 95 5

Detection—UV (220 and 254 nm) and ELSD Method D

Experiments were performed on a SHIMADZU LCMS-2020 with aC18-reverse-phase column (50×3 mm Shim-Pack XR-ODS, 2.2 μm particlesize), elution with solvent A: water+0.05% trifluoroacetic acid; solventB: acetonitrile+0.05% trifluoroacetic acid. Gradient:

Gradient-Time flow ml/min % A % B 0.00 1.2 95 5 3.50 1.2 30 70 3.70 1.20 100 4.50 1.2 0 100 4.75 1.2 95 5

Detection—UV (220 and 254 nm) and ELSD Method E

Experiments were performed on a SHIMADZU LCMS-2020 with aC18-reverse-phase column (50×3 mm Shim-Pack XR-ODS, 2.2 μm particlesize), elution with solvent A: water+0.05% trifluoroacetic acid; solventB: acetonitrile+0.05% trifluoroacetic acid. Gradient:

Gradient-Time flow ml/min % A % B 0.00 1.2 95 5 3.50 1.2 40 60 3.70 1.20 100 4.70 1.2 0 100 4.75 1.2 95 5

Detection—UV (220 and 254 nm) and ELSD Method F

Experiments were performed on a SHIMADZU LCMS-2020 with aC18-reverse-phase column (50×3 mm Shim-Pack XR-ODS, 2.2 μm particlesize), elution with solvent A: water+0.05% trifluoroacetic acid; solventB: acetonitrile+0.05% trifluoroacetic acid. Gradient:

Gradient-Time flow ml/min % A % B 0.00 1.2 70 30 3.50 1.2 30 70 3.70 1.20 100 4.50 1.2 0 100 4.75 1.2 95 5

Detection—UV (220 and 254 nm) and ELSD Method G

Experiments were performed on a SHIMADZU 20A HPLC with aC18-reverse-phase column (50×2.1 mm Ascentis Express C18, 2.7 μmparticle size), elution with solvent A: water+0.05% trifluoroaceticacid; solvent B: acetonitrile+0.05% trifluoroacetic acid. Gradient:

Gradient-Time flow ml/min % A % B 0.00 1.0 95 5 1.10 1.0 0 100 1.60 1.00 100 1.70 1.0 95 5

Detection—UV (220 and 254 nm) and ELSD Method H

Experiments were performed on a SHIMADZU LCMS-2020 with aC18-reverse-phase column (50×3 mm Shim-Pack XR-ODS, 2.2 μm particlesize), elution with solvent A: water+0.05% trifluoroacetic acid; solventB: acetonitrile+0.05% trifluoroacetic acid. Gradient:

Gradient-Time flow ml/min % A % B 0.00 1.2 95 5 1.10 1.2 0 100 1.70 1.20 100 1.75 1.2 95 5

Detection—UV (220 and 254 nm) and ELSD Method I

Experiments were performed on a SHIMADZU 20A HPLC with PoroshellHPH-C₁₈, column (50×3 mm, 2.7 μm particle size), elution with solvent A:water/5 mM NH₄HCO₃; solvent B: acetonitrile. Gradient:

Gradient-Time flow ml/min % A % B 0.00 1.2 90 10 1.10 1.2 5 95 1.60 1.25 95 1.70 1.2 90 10

Detection—UV (220 and 254 nm) and ELSD Method J

Experiments were performed on a SHIMADZU LCMS-2020 with aC18-reverse-phase column (50×3 mm Kinetex XB-C₁₈, 2.6 μm particle size),elution with solvent A: water+0.05% trifluoroacetic acid; solvent B:acetonitrile+0.05% trifluoroacetic acid. Gradient:

Gradient-Time flow ml/min % A % B 0.00 1.5 95 5 1.20 1.5 0 100 1.70 1.50 100 1.80 1.5 95 5

Detection—UV (220 and 254 nm) and ELSD Method K

Experiments were performed on a SHIMADZU LCMS-2020 with aC18-reverse-phase column (50×3 mm Shim-Pack XR-ODS, 2.2 μm particlesize), elution with solvent A: water+0.05% trifluoroacetic acid; solventB: acetonitrile+0.05% trifluoroacetic acid. Gradient:

Gradient-Time flow ml/min % A % B 0.00 1.0 95 5 2.20 1.0 0 100 3.20 1.00 100 3.30 1.0 95 5

Detection—UV (220 and 254 nm) and ELSD Method L

Experiments were performed on a SHIMADZU LCMS-2020 with aC18-reverse-phase column (50×2.1 mm Kinetex XB-C₁₈ 100A, 2.6 μm particlesize), elution with solvent A: water+0.05% trifluoroacetic acid; solventB: acetonitrile+0.05% trifluoroacetic acid. Gradient:

Gradient-Time flow ml/min % A % B 0.00 1.0 95 5 1.10 1.0 0 100 1.60 1.00 100 1.70 1.0 95 5

Detection—UV (220 and 254 nm) and ELSD LIST OF COMMON ABBREVIATIONS

-   ACN Acetonitrile-   Brine Saturated aqueous sodium chloride solution-   CH₃OD Deuterated Methanol-   CDCl₃ Deuterated Chloroform-   DCM Dichloromethane-   DIEA or DIPEA Diisopropylethylamine-   DMA Dimethylacetamide-   DMAP 4-Dimethylaminopyridine-   DMF Dimethylformamide-   DMSO Dimethylsulfoxide-   DMSO-d6 Deuterated dimethylsulfoxide-   EDC or EDCI 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide-   EtOAc Ethyl acetate-   EtOH Ethanol-   FA Formic Acid-   HOAc Acetic acid-   g Gram-   h hour-   HATU (O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium    hexafluorophosphate)-   HCl Hydrochloric acid-   HOBt Hydroxybenzotriazole-   HPLC High performance liquid chromatography-   IMS Industrial methylated spirits-   L Liter-   LCMS Liquid chromatography-mass spectrometry-   LiHMDS or LHMDS Lithium hexamethydisylazide-   MDAP Mass directed automated purification-   MeCN Acetonitrile-   MeOH Methanol-   min minute-   mg Milligram-   mL Millilitre-   NMR Nuclear magnetic resonance spectroscopy-   Pd₂(dba)₃.CHCl₃ Tris(dibenzylideneacetone)dipalladium(0)-chloroform    adduct-   PE Petroleum ether-   Prep-HPLC Preparative high performance liquid chromatography-   SCX-2 Strong cation exchange-   TBAF Tetra-n-butylammonium fluoride-   THF Tetrahydrofuran-   TFA Trifluoroacetic acid-   Xantphos 4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene

Intermediate 1 Error! Objects Cannot be Created from Editing Field CodesN-(5-(5-bromo-2-(difluoromethoxy)phenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamideStep 1: Synthesis of 4-bromo-1-(difluoromethoxy)-2-iodobenzene

To a solution of 4-bromo-2-iodophenol (282 g, 943 mmol) inN,N-dimethylformamide (2000 mL) and water (500 mL) was added sodium2-chloro-2,2-difluoroacetate (216 g, 1.42 mol) and Cs₂CO₃ (617 g, 1.89mol). The reaction vessel was equipped with a gas outlet for CO₂release. The resulting mixture was stirred overnight at 120° C., allowedto cool to room temperature and poured into ice water (3000 mL). Theresulting solution was extracted with ethyl acetate (3×1500 mL) and theorganic layers were combined. The ethyl acetate extracts were washedwith brine (1000 mL), dried over anhydrous sodium sulfate andconcentrated under reduced pressure. The residue was purified by flashchromatography on silica gel eluting with ethyl acetate/petroleum ether(1/10) to afford 300 g (91%) of4-bromo-1-(difluoromethoxy)-2-iodobenzene as a yellow oil. ¹H NMR (300MHz, CDCl₃) δ 7.96 (dd, J=5.7 Hz, 2.4 Hz, 1H), 7.45 (dd, J=8.7 Hz, 2.4Hz, 1H), 7.03 (d, J=8.7 Hz, 1H), 6.39 (t, J=72.9 Hz, 1H).

Step 2: Synthesis of5-[5-bromo-2-(difluoromethoxy)phenyl]-4-nitro-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-pyrazoleError! Objects Cannot be Created from Editing Field Codes

To a solution of4-nitro-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-pyrazole (100 g, 411mmol) in anhydrous THF (1000 mL) was added dropwise to a solution ofLiHMDS (490 mL, 1.0 mol/L in THF) with stirring at −70° C. undernitrogen. The resulting solution was stirred for 1 h at −50° C. and thencooled to −70° C. ZnCl₂ (500 mL, 0.7 mol/L in THF) was added dropwise at−70° C. The resulting solution was allowed to warm to room temperatureand stirred at room temperature for 1 h. To the mixture was added4-bromo-1-(difluoromethoxy)-2-iodobenzene (150 g, 860 mmol), Pd(PPh₃)₄(24.0 g, 20.8 mmol). The resulting solution was heated at refluxtemperature overnight, allowed to cool to room temperature, andconcentrated under reduced pressure. This reaction at this scale wasrepeated one more time, and the crude products from the two runs werecombined for purification. The residue was purified by flashchromatography on silica gel eluting with ethyl acetate/petroleum ether(1/20). The appropriate fractions were combined and concentrated underreduced pressure. This resulted in 300 g (79%) of5-[5-bromo-2-(difluoromethoxy)phenyl]-4-nitro-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-pyrazoleas a light yellow solid in all. ¹H NMR (300 MHz, CDCl₃) δ 8.27 (s, 1H),7.68 (dd, J=8.7, 2.4 Hz, 1H), 7.62 (d, J=2.4 Hz, 1H), 7.19 (d, J=8.4 Hz,1H), 6.39 (t, J=72.5 Hz, 1H), 5.44-5.19 (m, 2H), 3.72-3.54 (m, 2H),0.94-0.89 (m, 2H), 0.02 (s, 9H).

Step 3: Synthesis of5-(5-bromo-2-(difluoromethoxy)phenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-amineError! Objects Cannot be Created from Editing Field Codes

To a solution of5-(5-bromo-2-(difluoromethoxy)phenyl)-4-nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole(50.1 g, 108 mmol) in ethanol (2000 mL) and water (200 mL) was addediron powder (60.1 g, 1.07 mol) and NH₄Cl (28.0 g, 0.523 mol). Thereaction mixture was stirred at reflux temperature for 3 h undernitrogen. The solids were filtered out, and washed with ethanol (100mL). The filtrate was concentrated under reduced pressure. The residuewas dissolved in 3000 mL of ethyl acetate. The ethyl acetate solutionwas washed with 1×500 mL of brine, dried over anhydrous sodium sulfateand concentrated under reduced pressure to give 50.1 g of crude5-(5-bromo-2-(difluoromethoxy)phenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-amineas a yellow oil. The crude product was used for next step withoutfurther purification. LC/MS (Method G, ESI): [M+H]⁺=434.2, R_(T)=0.93min.

Step 4: Synthesis ofN-(5-(5-bromo-2-(difluoromethoxy)phenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

To a solution of5-(5-bromo-2-(difluoromethoxy)phenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-amine(50.1 g, 115 mmol) in DMA (1500 mL) was addedpyrazolo[1,5-a]pyrimidine-3-carboxylic acid (32.1 g, 196.0 mmol), PyAOP(102 g, 196 mmol), DMAP (1.41 g, 11.0 mmol) and DIPEA (44.1 g, 0.341mol). The resulting solution was stirred for 3 h at 60° C. in an oilbath, and then allowed to cool to room temperature. The reaction mixturewas then partitioned between water/ice (2000 mL) and ethyl acetate (2000mL). The aqueous phase was extracted with ethyl acetate (2×). Theorganic layers were combined, washed with brine (1000 mL), dried overanhydrous sodium sulfate and concentrated under reduced pressure. Theresidue was purified by flash chromatography on silica gel eluting withethyl acetate/petroleum ether (4:1). The appropriate fractions werecombined and concentrated under reduced pressure. Water (150 mL) wasadded to the residue and the mixture was stirred in water for 1 h atroom temperature. The solid was collected by filtration and air-dried toafford 60.1 g (91%) ofN-(5-(5-bromo-2-(difluoromethoxy)phenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamideas a light yellow solid. LC/MS (Method G, ESI): [M+H]⁺=579.1 & 581.1,R_(T)=1.10 min. ¹H NMR (300 MHz, CDCl₃) δ 9.62 (s, 1H), 8.80 (dd, J=6.9,1.7 Hz, 1H), 8.73 (s, 1H), 8.53 (dd, J=4.2, 1.7 Hz, 1H), 8.38 (s, 1H),7.79 (d, J=2.4 Hz, 1H), 7.67 (dd, J=8.8, 2.5 Hz, 1H), 7.29 (d, J=1.4 Hz,1H), 7.00 (dd, J=6.9, 4.2 Hz, 1H), 6.43 (t, J=72.6 Hz, 1H), 5.53-5.27(m, 2H), 3.73-3.50 (m, 2H), 0.88 (ddd, J=9.5, 6.4, 4.4 Hz, 2H), 0.00 (s,9H).

Intermediate 2 Error! Objects Cannot be Created from Editing Field CodesN-[3-[5-bromo-2-(difluoromethoxy)phenyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide

N-[5-[5-bromo-2-(difluoromethoxy)phenyl]-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide(Intermediate 1, 5.00 g, 8.63 mmol) was treated with HCl/dioxane (150mL, 4 M) overnight at room temperature. The resulting mixture wasconcentrated under reduced pressure. This resulted in 3.80 g ofN-[3-[5-bromo-2-(difluoromethoxy)phenyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamideas a yellow solid. The purity of the intermediate was sufficient for usein the next step without further purification. LC/MS (Method I, ESI):[M+H]⁺=449.0, R_(T)=1.02 min. ¹H NMR (400 MHz, CD₃OD) δ 9.11 (dd, J=6.8,1.6 Hz, 1H), 8.67-8.64 (m, 2H), 8.32 (s, 1H), 7.80 (d, J=2.4 Hz, 1H),7.72 (dd, J=8.8, 2.4 Hz, 1H), 7.37 (d, J=8.8 Hz, 1H), 7.23 (dd, J=7.0,4.2 Hz, 1H), 6.81 (t, J=73.2 Hz, 1H).

Intermediate 3 Error! Objects Cannot be Created from Editing Field CodesN-[3-[2-(difluoromethoxy)-5-iodophenyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamideStep 1: Synthesis ofN-[5-[2-(difluoromethoxy)-5-iodophenyl]-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamideError! Objects Cannot be Created from Editing Field Codes

To a solution ofN-[5-[5-bromo-2-(difluoromethoxy)phenyl]-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide(100 mg, 0.173 mmol) in t-BuOH (2 mL) was addedN,N-dimethylethane-1,2-diamine (2.28 mg, 0.0259 mmol), Nat (155 mg, 1.04mmol), CuI (4.93 mg, 0.026 mmol) under nitrogen. The resulting solutionwas stirred for 14 h at 120° C. in an oil bath under nitrogen beforebeing cooled to room temperature. The resulting mixture was concentratedunder reduced pressure. The residue was purified by flash chromatographyon silica gel eluting with ethyl acetate/petroleum ether (1/1) to afford80 mg (74%) ofN-[5-[2-(difluoromethoxy)-5-iodophenyl]-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamideas a yellow solid. LC/MS (Method J, ESI): [M+H]⁺=627.1, R_(T)=1.31 min.

Step 2: Synthesis ofN-[3-[2-(difluoromethoxy)-5-iodophenyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamideError! Objects Cannot be Created from Editing Field Codes

N-[5-[2-(difluoromethoxy)-5-iodophenyl]-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide(80.0 mg, 0.128 mmol) was treated with CF₃CO₂H (3.0 mL) for 30 min atroom temperature. The resulting mixture was concentrated under reducedpressure. The residue was dissolved in water. Saturated sodiumbicarbonate was slowly added until the solution was adjusted pH 8. Thesolid was collected by filtration. The solid was purified by flashchromatography on silica gel eluting with ethyl acetate/petroleum ether(2/1) to give 23.0 mg (36%) ofN-[3-[2-(difluoromethoxy)-5-iodophenyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamideas a light yellow solid. LC/MS (Method K, ESI): [M+H]⁺=497.1, R_(T)=1.74min. ¹H NMR (300 MHz, CD₃OD) δ 9.08 (dd, J=6.9, 1.5 Hz, 1H), 8.65-8.61(m, 2H), 8.27 (s, 1H), 7.94 (s, 1H), 7.87 (d, J=8.7 Hz, 1H), 7.21-7.18(m, 2H), 6.78 (t, J=73.2 Hz, 1H).

Intermediate 4 Error! Objects Cannot be Created from Editing Field CodesN-(3-(5-((1R,2R)-2-cyanocyclopropyl)-2-(difluoromethoxy)phenyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamideStep 1: Synthesis ofN-[5-[5-(2-cyanocyclopropyl)-2-(difluoromethoxy)phenyl]-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamideError! Objects Cannot be Created from Editing Field Codes

To a solution ofN-[5-[5-bromo-2-(difluoromethoxy)phenyl]-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide(Intermediate 1, 1.00 g, 1.73 mmol) in dioxane (15 mL) and water (3.0mL) was added potassium (2-cyanocyclopropyl)trifluoroborate (449 mg,2.60 mmol), Pd(dppf)Cl₂.CH₂Cl₂ (141 mg, 0.173 mmol, 0.10 equiv) andCs₂CO₃ (1.13 g, 3.47 mmol, 2.01 equiv) under nitrogen. The resultingsolution was stirred overnight at 80° C. in an oil bath. The resultingmixture was concentrated under reduced pressure. The reaction at thisscale was repeated five times, and the crude products from 5 operationswere combined together for purification. The residue was passed througha short pad of silica gel eluting with ethyl acetate/petroleum ether(6/4). The appropriate fractions were combined and concentrated underreduced pressure to afford 2.5 g (purity=85% by LCMS at 254 nm) ofN-[5-[5-(2-cyanocyclopropyl)-2-(difluoromethoxy)phenyl]-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamideas a yellow solid. The quality of the intermediate was sufficient fornext step. No further purification was required. LC/MS (Method G, ESI):[M+H]⁺=566.2, R_(T)=1.07 min.

Step 2:N-(3-[5-[(1R,2R)-2-cyanocyclopropyl]-2-(difluoromethoxy)phenyl]-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamideError! Objects Cannot be Created from Editing Field Codes

N-[5-[5-(2-cyanocyclopropyl)-2-(difluoromethoxy)phenyl]-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide(2.90 g, 5.13 mmol) was treated with trifluoroacetic acid (10 mL) indichloromethane (20 mL) overnight at room temperature. The resultingmixture was concentrated under vacuum. The pH of the residue wasadjusted to >7 with DIEA. The resulting mixture was concentrated undervacuum. Water was added and the mixture was stirred for 1 h. The solidswere collected by filtration. The crude product (2.30 g) was purified byPrep-HPLC with the following conditions: Column, XBridge Shield RP18 OBDColumn, 19*150 mm Sum 13 nm; mobile phase, Water with 0.05% NH₄OH andMeCN (30.0% MeCN up to 45.0% in 9 min); Detector, UV 254 nm. The racemicproduct was separated by Prep-SFC with the following conditions: Column:CHIRALPAK-IC-SFC-02, 5 cm*25 cm(5 um); Mobile Phase A:CO₂:50, MobilePhase B:EtOH:50; Flow rate: 180 mL/min; 220 nm; R_(T1)=13.97 min (thefirst peak); R_(T2)=17.84 min (the second peak) to afford two fractions:

Fraction 1 (R,R-isomer): The first peak was the desired fraction andfurther purified by re-crystallization from isopropanol. This resultedin 340 mg (15%) ofN-(3-[5-[(1R,2R)-2-cyanocyclopropyl]-2-(difluoromethoxy)phenyl]-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamideas an off-white solid. ¹H NMR (300 MHz, CD₃OD) δ 9.09 (dd, J=7.1, 1.7Hz, 1H), 8.67-8.62 (m, 2H), 8.27 (s, 1H), 7.43-7.35 (m, 3H), 7.21 (dd,J=6.9, 4.2 Hz, 1H), 6.76 (t, J=73.8 Hz, 1H), 2.79-2.72 (m, 1H),1.94-1.88 (m, 1H), 1.68-1.63 (m, 1H), 1.62-1.56 (m, 1H).

Fraction 2 (S,S-isomer): The second peak was got 474 mg (21%) ofN-(3-[5-[(1S,2S)-2-cyanocyclopropyl]-2-(difluoromethoxy)phenyl]-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamideas a white solid. ¹H NMR (300 MHz, CD₃OD) δ 9.09 (dd, J=7.1, 1.7 Hz,1H), 8.67-8.62 (m, 2H), 8.27 (s, 1H), 7.43-7.35 (m, 3H), 7.21 (dd,J=6.9, 4.2 Hz, 1H), 6.76 (t, J=73.8 Hz, 1H), 2.79-2.72 (m, 1H),1.94-1.88 (m, 1H), 1.68-1.63 (m, 1H), 1.62-1.56 (m, 1H).

Intermediate 5 Error! Objects Cannot be Created from Editing Field CodesN-[3-[5-cyclopropyl-2-(difluoromethoxy)phenyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamideStep 1: Synthesis ofN-[3-[5-cyclopropyl-2-(difluoromethoxy)phenyl]-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamideError! Objects Cannot be Created from Editing Field Codes

To a solution ofN-(5-(5-bromo-2-(difluoromethoxy)phenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide(Intermediate 1, 1.40 g, 2.41 mmol) in dioxane (15 mL) and water (3.0mL) was added cyclopropylboronic acid (314 mg, 3.66 mmol),Pd(dppf)Cl₂—CH₂Cl₂ (200 mg, 0.245 mmol) and Cs₂CO₃ (1.56 g, 4.79 mmol)under nitrogen. The reaction mixture was stirred overnight at 80° C.under nitrogen. The resulting mixture was concentrated under reducedpressure. The residue was passed through a short pad of silica geleluting with dichloromethane/methanol (94/6). The appropriate fractionswere combined and concentrated under reduced pressure to give 1.40 g(purity=˜85% at 254 nm) ofN-[3-[5-cyclopropyl-2-(difluoromethoxy)phenyl]-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamideas a dark red solid. LC/MS (Method G, ESI): [M+H]⁺=541.2, R_(T)=1.12min. The intermediate was used without further purification.

Step 2: Synthesis ofN-[3-[5-cyclopropyl-2-(difluoromethoxy)phenyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamideError! Objects Cannot be Created from Editing Field Codes

N-[3-[5-cyclopropyl-2-(difluoromethoxy)phenyl]-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide(145 mg) from previous step was treated with HCl/dioxane (5.0 mL, 4 M)for 2 h at 25° C. The solution was concentrated under reduced pressure.The residue was purified by Prep-HPLC with the following conditions:Column: Xbridge C18, 19*150 mm, 5 um; Mobile Phase A: Water/0.05%NH₄HCO₃, Mobile Phase B: ACN; Flow rate: 30 mL/min; Gradient: 20% B to85% B in 10 min; 254 nm to obtain 44.9 mg (41%) ofN-[3-[5-cyclopropyl-2-(difluoromethoxy)phenyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamideas a yellow solid. LC/MS (Method H, ESI): [M+H]⁺=411.2, R_(T)=1.14 min.¹H NMR (300 MHz, CD₃OD) δ 9.09 (dd, J=6.9, 1.5 Hz, 1H), 8.63-8.61 (m,2H), 8.27 (s, 1H), 7.28-7.25 (m, 3H), 7.20 (dd, J=7.2, 4.2 Hz, 1H), 6.68(t, J=73.8 Hz, 1H), 2.04-1.95 (m, 1H), 1.03-0.97 (m, 2H), 0.79-0.71 (m,2H)

Intermediate 6 Error! Objects Cannot be Created from Editing Field CodesN-[3-[2-(difluoromethoxy)-5-[4-(dimethylcarbamoyl)phenoxy]phenyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamideStep 1: Synthesis ofN-[5-[2-(difluoromethoxy)-5-[4-(dimethylcarbamoyl)phenoxy]phenyl]-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamideError! Objects Cannot be Created from Editing Field Codes

To a solution ofN-5-[5-bromo-2-(difluoromethoxy)phenyl]-1-[2-(trimethylsilyl)ethoxy]methyl-1H-pyrazol-4-ylpyrazolo[1,5-a]pyrimidine-3-carboxamide(Intermediate 1, 1.17 g, 2.02 mmol) in toluene (10 mL) was added4-hydroxy-N,N-dimethylbenzamide (0.400 g, 2.42 mmol), Cs₂CO₃ (0.790 g,2.43 mmol), [PdCl(allyl)]₂ (37.0 mg, 0.101 mmol) and t-BuBrettPhos (98.0mg, 0.202 mmol) under nitrogen. The reaction mixture was stirredovernight at 90° C. The resulting mixture was concentrated under reducedpressure. The residue was purified by flash chromatography on silica geleluting with dichloromethane/methanol (95/5) to give 1.3 g (81%) ofN-[5-[2-(difluoromethoxy)-5-[4-(dimethylcarbamoyl)phenoxy]phenyl]-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamideas a yellow oil. LC/MS (Method H, ESI): [M+H]⁺=664.4, R_(T)=1.36 min.

Step 2: Synthesis ofN-[3-[2-(difluoromethoxy)-5-[4-(dimethylcarbamoyl)phenoxy]phenyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamideError! Objects Cannot be Created from Editing Field Codes

To a solution ofN-[5-[2-(difluoromethoxy)-5-[4-(dimethylcarbamoyl)phenoxy]phenyl]-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide(139 mg, 0.209 mmol) in MeOH (3.0 mL) was added concentratedhydrochloric acid (1.5 mL, 12M). The reaction mixture was stirred for 2h at 25° C. and concentrated under reduced pressure. The residue wasneutralized with DIPEA. The resulting mixture was concentrated underreduced pressure. The residue was purified by flash chromatography onsilica gel eluting with dichloromethane/methanol (95/5) to obtain 28 mg(25%) ofN-[3-[2-(difluoromethoxy)-5-[4-(dimethylcarbamoyl)phenoxy]phenyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamideas an off-white solid. LC/MS (Method H, ESI): [M+H]⁺=534.2, R_(T)=1.09min. ¹H NMR (300 MHz, DMSO-d₆) δ 13.05 (s, 1H), 9.73 (s, 1H), 9.35 (dd,J=7.1, 1.7 Hz, 1H), 8.70 (dd, J=4.2, 1.5 Hz, 1H), 8.69 (s, 1H), 8.22 (s,1H), 7.47 (d, J=9.3 Hz, 1H), 7.39 (d, J=8.4 Hz, 2H), 7.32-7.25 (m, 3H),7.06 (d, J=8.7 Hz, 2H), 7.18 (t, J=73.8 Hz, 1H), 2.94 (s, 6H)

Intermediate 7 Error! Objects Cannot be Created from Editing Field CodesN-[3-[2,5-bis(difluoromethoxy)phenyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamideStep 1: Synthesis of 1-(benzyloxy)-4-(difluoromethoxy)benzene Error!Objects Cannot be Created from Editing Field Codes

Into a 3000-mL round-bottom flask purged and maintained with an inertatmosphere of nitrogen, was placed N,N-dimethylformamide (1500 mL),4-(benzyloxy)phenol (200 g, 999 mmol) and Cs₂CO₃ (651 g, 1.99 mol). Thereaction vessel was equipped with an outlet for CO₂ release. This wasfollowed by the addition of sodium 2-chloro-2,2-difluoroacetate (228 g,1.50 mol, 1.50 equiv) in several batches at 120° C. After completion ofthe sodium 2-chloro-2,2-difluoroacetate addition, the reaction wasstirred at 120° C. in an oil bath until gas evolution ceased (˜1 h), andthen allowed to cool to room temperature. The reaction mixture wasslowly added to 3000 mL of water/ice with stirring. The resultingmixture was extracted with ethyl acetate (3×4000 mL). The organic layerswere combined and dried over anhydrous sodium sulfate and concentratedunder reduced pressure. The residue was purified by flash chromatographyon silica gel eluting with ethyl acetate/petroleum ether (1/19). Theappropriate fractions were combined and concentrated under reducedpressure. This reaction was repeated four times. This resulted in 450 g(36%) of 1-(benzyloxy)-4-(difluoromethoxy)benzene as a white solid intotal.

Step 2: Synthesis of 4-(difluoromethoxy)phenol Error! Objects Cannot beCreated from Editing Field Codes

Into a 3000-mL round-bottom flask was placed methanol (1500 mL),1-(benzyloxy)-4-(difluoromethoxy)benzene (140 g, 559 mmol) and 10%Palladium carbon (15 g, 141 mmol). The resulting mixture was stirredunder hydrogen (˜45 psi) overnight at room temperature. The catalystswere filtered out. The filtrate was concentrated under reduced pressure.This reaction was repeated three times. This resulted in 300 g (78%) of4-(difluoromethoxy)phenol as a yellow oil.

Step 3: Synthesis of 2-bromo-4-(difluoromethoxy)phenol Error! ObjectsCannot be Created from Editing Field Codes

Into a 1000-mL round-bottom flask was placed acetic acid (500 mL),4-(difluoromethoxy)phenol (50 g, 312 mmol) and NBS (55.6 g, 312 mmol).The reaction mixture was stirred for 1 h at 15° C. The resulting mixturewas then added slowly to 1000 mL of water/ice with stirring. Theresulting solution was extracted with ethyl acetate (3×1000 mL). Theorganic layers were combined, dried over anhydrous sodium sulfate andconcentrated under reduced pressure. The residue was purified by flashchromatography on silica gel eluting with dichloromethane/petroleumether (30/70). The appropriate fractions were collected and concentratedunder reduced pressure. This resulted in 50 g (67%) of2-bromo-4-(difluoromethoxy)phenol as a light yellow oil.

Step 4: Synthesis of 2-bromo-1,4-bis(difluoromethoxy)benzene Error!Objects Cannot be Created from Editing Field Codes

Into a 2000-mL round-bottom flask, was placed CH₃CN (500 mL), water (500mL), 2-bromo-4-(difluoromethoxy)phenol (54 g, 226 mmol) and potassiumhydroxide (94 g, 1.68 mol). The flask was placed in an ice batch and thereaction mixture was stirred for 30 min in an ice batch. Diethyl(bromodifluoromethyl)phosphonate (120 g, 449 mmol) was then addeddropwise to the reaction mixture at 0° C. Upon completion of diethyl(bromodifluoromethyl)phosphonate addition, the reaction mixture wasstirred for 1 h in a water/ice bath. The resulting solution wasextracted with ethyl acetate (3×300 mL). The organic layers werecombined and dried over anhydrous sodium sulfate and concentrated underreduced pressure. The residue was purified by flash chromatography onsilica gel eluting with ethyl acetate/petroleum ether (1/19), and theappropriate fractions were collected and concentrated under reducedpressure. This resulted in 54 g (83%) of2-bromo-1,4-bis(difluoromethoxy)benzene as light yellow oil.

Step 5: Synthesis of5-[2,5-bis(difluoromethoxy)phenyl]-4-nitro-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-pyrazoleError! Objects Cannot be Created from Editing Field Codes

Into a 1000-mL round-bottom flask purged and maintained with an inertatmosphere of nitrogen, was placed DMA (500 mL), potassium carbonate(112 g, 810 mmol),4-nitro-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-pyrazole (66 g, 271mmol), 2-bromo-1,4-bis(difluoromethoxy)benzene (79 g, 273 mmol),2,2-dimethylpropanoic acid (8.3 g, 81.3 mmol), Pd(OAc)₂ (6.0 g, 26.7mmol) and bis(adamantan-1-yl)(butyl)phosphane (19 g, 52.9 mmol, 0.195equiv). The reaction mixture was stirred at 120° C. overnight in an oilbath, and allowed to cool to room temperature. The reaction mixture wasthen added to 1000 mL of water/ice with stirring. The resulting solutionwas extracted with ethyl acetate (3×1000 mL). The organic layers werecombined and dried over anhydrous sodium sulfate and concentrated underreduced pressure. The residue was purified by flash chromatography onsilica gel eluting with ethyl acetate/petroleum ether (1/1). Theappropriate fractions were collected and concentrated under reducedpressure. This resulted in 100 g (82%) of5-[2,5-bis(difluoromethoxy)phenyl]-4-nitro-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-pyrazoleas a solid.

Step 6: Synthesis of5-[2,5-bis(difluoromethoxy)phenyl]-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-pyrazol-4-amineError! Objects Cannot be Created from Editing Field Codes

Into a 3000-mL 3-necked round-bottom flask was placed ethanol (1500 mL),water (150 mL),5-[2,5-bis(difluoromethoxy)phenyl]-4-nitro-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-pyrazole(100.00 g, 221 mmol), iron powder (124 g, 2.22 mol) and NH₄Cl (59.2 g,1.11 mol). The resulting mixture was stirred at reflux temperature in anoil bath for 2 h before being cooled to room temperature. The solidswere filtered off, and washed with ethanol. The filtrate wasconcentrated under reduced pressure. The residue was dissolved in 3000mL of ethyl acetate. The ethyl acetate solution was washed with 1×1000mL of brine, dried over anhydrous sodium sulfate and concentrated underreduced pressure. This resulted in 100 g of crude5-[2,5-bis(difluoromethoxy)phenyl]-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-pyrazol-4-amineas light yellow oil, which was used directly without purification.

Step 7: Synthesis ofN-[5-[2,5-bis(difluoromethoxy)phenyl]-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamideError! Objects Cannot be Created from Editing Field Codes

Into a 2000-mL round-bottom flask was placed DMA (1000 mL),5-[2,5-bis(difluoromethoxy)phenyl]-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-pyrazol-4-aminefrom previous step, pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (58.06g, 355.9 mmol), 7-Azabenzotriazol-1-yloxy)tripyrrolidinophosphoniumhexafluorophosphate (PyAOP) (185.56 g, 355.9 mmol),4-dimethylaminopyridine (2.90 g, 23.7 mmol) and DIPEA (92.0 g, 712mmol). The resulting solution was stirred overnight at 65° C. in an oilbath. The reaction mixture was then added slowly to 2000 mL of waterwith stirring. The resulting solution was extracted with ethyl acetate(3×2000 mL). The combined organic phases were washed with 1000 mL ofbrine, dried over anhydrous sodium sulfate and concentrated in underpressure. The residue was purified by flash chromatography on silica geleluting with ethyl acetate/petroleum ether (40/60). The appropriatefractions were combined and concentrated under reduced pressure toafford 120 g ofN-[5-[2,5-bis(difluoromethoxy)phenyl]-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamideas a white solid.

Step 8: Synthesis ofN-[3-[2,5-bis(difluoromethoxy)phenyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamideError! Objects Cannot be Created from Editing Field Codes

Into a 2000-mL round-bottom flask was placed methanol (800 mL),concentrated hydrochloric acid (400 mL, 12N) andN-[5-[2,5-bis(difluoromethoxy)phenyl]-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide(80 g, 141 mmol). The resulting solution was stirred for 4 h at 25° C.The solids were collected by filtration. The solids were added to a 1 Lflask and H₂O (200 mL) was added. A saturated NaHCO₃ aqueous solutionwas added dropwise with stirring until the solution reached pH-8. Thesolids were collected by filtration, washed with water and dried toafford 55 g (89%) ofN-[3-[2,5-bis(difluoromethoxy)phenyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamideas a light yellow solid. ¹H NMR (300 MHz, CD₃OD) δ 9.08 (dd, J=7.2, 1.5Hz, 1H), 8.65-8.61 (m, 2H), 8.28 (s, 1H), 7.46 (d, J=9.0 Hz, 1H), 7.40(d, J=3.0 Hz, 1H), 7.34 (dd, J=8.9, 2.9 Hz, 1H), 7.19 (dd, J=6.7, 4.4Hz, 1H), 6.87 (t, J=73.7 Hz, 1H), 6.73 (t, J=73.7 Hz, 1H).

Example 1

N-(3-(5-((1R,2R)-2-cyanocyclopropyl)-2-(difluoromethoxy)phenyl)-1-(2-(dimethylamino)-2-oxoethyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

To a solution ofN-(3-(5-((1R,2R)-2-cyanocyclopropyl)-2-(difluoromethoxy)phenyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide(Intermediate 4, 100 mg, 0.230 mmol) in DMF (10 mL) was added Cs₂CO₃(160 mg, 0.491 mmol). This was followed by the addition of2-bromo-N,N-dimethylacetamide (80 mg, 0.482 mmol). The resulting mixturewas stirred for 30 min at 60° C. in an oil bath. The resulting mixturewas concentrated under reduced pressure. The residue was purified byflash chromatography on silica gel eluting with dichloromethane/methanol(8% MeOH) to give 20.9 mg (17%) ofN-(3-(5-((1R,2R)-2-cyanocyclopropyl)-2-(difluoromethoxy)phenyl)-1-(2-(dimethylamino)-2-oxoethyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamideas a white solid. LC/MS (Method A, ESI): [M+H]⁺=521.3, R_(T)=1.50 min;¹H NMR (400 MHz, DMSO-d₆) δ 9.76 (s, 1H), 9.35 (dd, J=6.8, 1.6 Hz, 1H),8.68 (s, 1H), 8.65 (dd, J=4.0, 1.6 Hz, 1H), 8.28 (s, 1H), 7.42-7.38 (m,3H), 7.29 (dd, J=7.0, 4.2 Hz, 1H), 7.23 (t, J=73.2 Hz, 1H), 5.20 (s,2H), 3.06 (s, 3H), 2.89 (s, 3H), 2.84-2.80 (m, 1H), 2.12-2.09 (m, 1H),1.66-1.61 (m, 1H), 1.54-1.50 (m, 1H).

Example 2 Error! Objects Cannot be Created from Editing Field CodesN-[3-[2-(difluoromethoxy)-5-iodophenyl]-1-[(dimethylcarbamoyl)methyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide

To a solution ofN-[3-[2-(difluoromethoxy)-5-iodophenyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide(Intermediate 3, 160 mg, 0.322 mmol) in DMF (4.0 mL) was added Cs₂CO₃(210 mg, 0.645 mmol). To this mixture was added2-bromo-N,N-dimethylacetamide (107 mg, 0.645 mmol). The resultingsolution was stirred for 4 h at 60° C. in an oil bath. The reactionmixture was partitioned between water and ethyl acetate. The aqueousphase was extracted ethyl acetate (2×). The organic layers werecombined, washed with water and brine successively, dried over anhydroussodium sulfate and concentrated under reduced pressure. The residue waspassed through a short pad of silica gel eluting withdichloromethane/methanol (90/10). The appropriate fractions werecombined and concentrated under reduced pressure. The crude product wasfurther purified by Prep-HPLC with the following conditions: Column,SunFire Prep C18 OBD Column, 19*150 mm Sum 10 nm; mobile phase, Water(0.1% FA) and ACN (25.0% ACN up to 44.0% in 12 min); Detector, UV254/220 nm to obtain 24.1 mg (13%) ofN-[3-[2-(difluoromethoxy)-5-iodophenyl]-1-[(dimethylcarbamoyl)methyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamideas a white solid. LC/MS (Method B, ESI): [M+H]+=582.2, R_(T)=2.92; ¹HNMR (400 MHz, CD₃OD) δ 9.11 (dd, J=6.8, 1.6 Hz, 1H), 8.67 (dd, J=4.4,1.6 Hz, 1H), 8.65 (s, 1H), 8.36 (s, 1H), 8.02 (d, J=2.4 Hz, 1H), 7.90(dd, J=8.8, 2.4 Hz, 1H), 7.24-7.21 (m, 2H), 6.82 (t, J=73.6 Hz, 1H),5.24 (s, 2H), 3.18 (s, 3H), 3.03 (s, 3H).

Example 3 Error! Objects Cannot be Created from Editing Field Codes2-amino-N-(3-(5-chloro-2-(difluoromethoxy)phenyl)-1-(2-(dimethylamino)-2-oxoethyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamideStep 1: Synthesis of tert-butylN-[3-([3-[5-chloro-2-(difluoromethoxy)phenyl]-1-[(dimethylcarbamoyl)methyl]-1H-pyrazol-4-yl]carbamoyl)pyrazolo[1,5-a]pyrimidin-2-yl]carbamateError! Objects Cannot be Created from Editing Field Codes

To a solution of tert-butylN-[3-([3-[5-chloro-2-(difluoromethoxy)phenyl]-1H-pyrazol-4-yl]carbamoyl)pyrazolo[1,5-a]pyrimidin-2-yl]carbamate(200 mg, 0.385 mmol) in DMF (5.0 mL) was added Cs₂CO₃ (251 mg, 0.770mmol) and 2-bromo-N,N-dimethylacetamide (63.0 mg, 0.379 mmol). Thereaction mixture was stirred for 16 h at 60° C. in an oil bath. Theresulting mixture was concentrated under reduced pressure. The residuewas purified by flash chromatography on silica gel eluting withdichloromethane/methanol (95/5). The appropriate fractions were combinedand concentrated under reduced pressure to give 200 mg (86%) oftert-butylN-[3-([3-[5-chloro-2-(difluoromethoxy)phenyl]-1-[(dimethylcarbamoyl)methyl]-1H-pyrazol-4-yl]carbamoyl)pyrazolo[1,5-a]pyrimidin-2-yl]carbamateas a yellow solid. LC/MS (Method H, ESI): [M+H]⁺=605.3, R_(T)=1.32 min.

Step 2: Synthesis of2-amino-N-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-[(dimethylcarbamoyl)methyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamideError! Objects Cannot be Created from Editing Field Codes

Tert-butylN-[3-([3-[5-chloro-2-(difluoromethoxy)phenyl]-1-[(dimethylcarbamoyl)methyl]-1H-pyrazol-4-yl]carbamoyl)pyrazolo[1,5-a]pyrimidin-2-yl]carbamate(100 mg, 0.165 mmol) was treated with HCl in dioxane (2.0 mL, 4M) for 2h at room temperature. The resulting mixture was concentrated underreduced pressure. The crude product was purified by Prep-HPLC with thefollowing conditions: Column, XBridge Shield RP18 OBD Column, Sum,19*150 mm; mobile phase, water (0.05% NH₃H₂O) and ACN (10% ACN up to 45%in 12 min); Detector, UV 220 nm to give 27.4 mg (33%) of2-amino-N-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-[(dimethylcarbamoyl)methyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamideas a white solid. LC/MS (Method A, ESI): [M+H]⁺=505.2, R_(T)=1.58 min;¹H NMR (300 MHz, DMSO-d₆) δ 9.55 (s, 1H), 8.93 (dd, J=6.8, 1.7 Hz, 1H),8.36 (dd, J=4.5, 1.5 Hz, 1H), 8.26 (s, 1H), 7.62 (dd, J=8.7, 2.7 Hz,1H), 7.54 (d, J=2.7 Hz, 1H), 7.45 (J=8.7 Hz, 1H), 7.26 (t, J=73.2 Hz,1H), 7.00 (dd, J=6.6, 4.5 Hz, 1H), 6.57 (s, 2H), 5.18 (s, 2H), 3.04 (s,3H), 2.87 (s, 3H).

Examples 4 & 5 Error! Objects Cannot be Created from Editing Field Codes(R)—N-(3-(5-(1,2-difluoroethyl)-2-(difluoromethoxy)phenyl)-1-(2-(dimethylamino)-2-oxoethyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide&(S)—N-(3-(5-(1,2-difluoroethyl)-2-(difluoromethoxy)phenyl)-1-(2-(dimethylamino)-2-oxoethyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamideStep 1: Synthesis ofN-[3-[2-(difluoromethoxy)-5-(1,2-dihydroxyethyl)phenyl]-1-[(dimethylcarbamoyl)methyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamideError! Objects Cannot be Created from Editing Field Codes

To a solution ofN-[3-[2-(difluoromethoxy)-5-ethenylphenyl]-1-[(dimethylcarbamoyl)methyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide(1.70 g, 3.53 mmol) in tetrahydrofuran (20 mL) and water (10 mL) wasadded 0504 (1.82 g, 7.16 mmol) and NMO (831 mg, 7.09 mmol). Theresulting solution was stirred for 2 h at room temperature. Theresulting solution was diluted with 30 mL of H₂O. The resulting solutionwas extracted with 3×50 mL of dichloromethane. The organic layers werecombined, washed with brine, dried and concentrated under reducedpressure. The residue was purified by flash chromatography on silica geleluting with dichloromethane/methanol (9/1). The appropriate fractionswere combined and concentrated under reduced pressure to give 700 mg(38%) ofN-[3-[2-(difluoromethoxy)-5-(1,2-dihydroxyethyl)phenyl]-1-[(dimethylcarbamoyl)methyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamideas a brown solid.

Step 2: Synthesis ofN-[3-[5-(1,2-difluoroethyl)-2-(difluoromethoxy)phenyl]-1-[(dimethylcarbamoyl)methyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamideError! Objects Cannot be Created from Editing Field Codes

To a solution ofN-[3-[2-(difluoromethoxy)-5-(1,2-dihydroxyethyl)phenyl]-1-[(dimethylcarbamoyl)methyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide(300 mg, 0.582 mmol) in dichloromethane was added DAST (374 mg, 2.32mmol). The reaction mixture was stirred for 2 h at room temperatureunder nitrogen. The reaction was then quenched by the addition of 10 mLof water. The pH value of the solution was adjusted to 7 with a sodiumbicarbonate aqueous solution (10%). The resulting mixture was extractedwith 3×10 mL of dichloromethane and the organic layers were combined andconcentrated under reduced pressure. The crude product was purified byPrep-HPLC with the following conditions: Column, XBridge BEH130 Prep C₁₈OBD Column, 19*150 mm Sum; mobile phase, Water (0.05% NH₃H₂O) and ACN(30% ACN up to 34% in 7 min); Detector, UV 254/220 nm to give 100 mg ofracemic mixture. The racemic mixture was separated by Chiral-Prep-HPLCwith the following conditions: Column, CHIRALPAK IA, 2.12*15 cm, Sum;mobile phase, Hexane/DCM=5/1 and ethanol (hold 50.0% ethanol—in 13 min);flow rate 16 mL/min, Detector, UV 220/254 nm afford two fractions:

Isomer 1: Eluted at 7.15 min, 12.4 mg (4%) ofN-[3-[5-(1,2-difluoroethyl)-2-(difluoromethoxy)phenyl]-1-[(dimethylcarbamoyl)methyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamideas a white solid. LC/MS (Method A, ESI): [M+H]⁺=520.2, R_(T)=1.70 min;¹H NMR (400 MHz, DMSO-d₆) δ 9.72 (s, 1H), 9.34 (dd, J=7.0, 1.4 Hz, 1H),8.68 (s, 1H), 8.66 (dd, J=4.0, 1.6 Hz, 1H), 8.29 (s, 1H), 7.65-7.61 (m,2H), 7.51 (d, J=8.0 Hz, 1H), 7.32 (t, J=73.2 Hz, 1H), 7.29 (dd, J=7.0,4.2 Hz, 1H), 6.11-5.84 (m, 1H), 5.22 (s, 2H), 4.88-4.68 (m, 2H), 3.06(s, 3H), 2.89 (s, 3H).

Isomer 2: Eluted at 9.66 min, 13.7 mg (5%) ofN-[3-[5-(1,2-difluoroethyl)-2-(difluoromethoxy)phenyl]-1-[(dimethylcarbamoyl)methyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamideas a white solid. LC/MS (Method A, ESI): [M+H]⁺=520.2, R_(T)=1.70 min;¹H NMR (400 MHz, DMSO-d₆) δ 9.72 (s, 1H), 9.34 (dd, J=7.0, 1.4 Hz, 1H),8.68 (s, 1H), 8.66 (dd, J=4.0, 1.6 Hz, 1H), 8.29 (s, 1H), 7.65-7.61 (m,2H), 7.51 (d, J=8.0 Hz, 1H), 7.32 (t, J=73.2 Hz, 1H), 7.29 (dd, J=7.0,4.2 Hz, 1H), 6.11-5.84 (m, 1H), 5.22 (s, 2H), 4.88-4.68 (m, 2H), 3.06(s, 3H), 2.89 (s, 3H).

Example 6 Error! Objects Cannot be Created from Editing Field CodesN-(3-(2-(difluoromethoxy)-5-(difluoromethyl)phenyl)-1-(2-(dimethylamino)-2-oxoethyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamideStep 1: Synthesis ofN-[3-[5-(1,1-difluoro-2-oxo-2-phenylethyl)-2-(difluoromethoxy)phenyl]-1-[(dimethylcarbamoyl)methyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamideError! Objects Cannot be Created from Editing Field Codes

To a solution ofN-[3-[5-bromo-2-(difluoromethoxy)phenyl]-1-[(dimethylcarbamoyl)methyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide(50.0 mg, 0.0936 mmol) in toluene (5.0 mL) was added2,2-difluoro-1-phenylethan-1-one (29.0 mg, 0.186 mmol),[2-(2-aminophenyl)phenyl](chloro)palladium; tricyclohexylphosphane (12.0mg, 0.0203 mmol) and K₃PO₄ (80.0 mg, 0.377 mmol) under nitrogen. Theresulting solution was stirred for 16 h at 100° C. in an oil bath. Thereaction mixture was cooled to room temperature. The resulting mixturewas concentrated under reduced pressure. The residue was purified byflash chromatography on silica gel eluting with dichloromethane/methanol(92/8) to give 23 mg (40%) ofN-[3-[5-(1,1-difluoro-2-oxo-2-phenylethyl)-2-(difluoromethoxy)phenyl]-1-[(dimethylcarbamoyl)methyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamideas a light yellow solid. LC/MS (Method I, ESI): [M+H]⁺=610.3, R_(T)=1.11min.

Step 2: Synthesis ofN-[3-[2-(difluoromethoxy)-5-(difluoromethyl)phenyl]-1-[(dimethylcarbamoyl)methyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamideError! Objects Cannot be Created from Editing Field Codes

To a solution ofN-[3-[5-(1,1-difluoro-2-oxo-2-phenylethyl)-2-(difluoromethoxy)phenyl]-1-[(dimethylcarbamoyl)methyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide(230 mg, 0.377 mmol) in toluene (30 mL) and water (5.0 mL) was addedpotassium hydroxide (43.0 mg, 0.766 mmol). The resulting solution wasstirred for 16 h at 100° C. in an oil bath. The reaction mixture wascooled to room temperature. The resulting solution was diluted with 50mL of H₂O. The resulting solution was extracted with 2×30 mL ofdichloromethane and the organic layers were combined and dried overanhydrous sodium sulfate and concentrated under reduced pressure. Theresidue was passed through a short pad of silica gel eluting withdichloromethane/methanol (95/5). The appropriate fractions were combinedand concentrated under reduced pressure. The residue was furtherpurified by Prep-HPLC with the following conditions: Column, XBridgeBEH130 Prep C18 OBD Column, 19*150 mm Sum; mobile phase, Water (0.05%NH₄OH) and ACN (29.0% ACN up to 42.0% in 7 min); Detector, uv 254/220 nmto obtain 23.7 mg (12%) ofN-[3-[2-(difluoromethoxy)-5-(difluoromethyl)phenyl]-1-[(dimethylcarbamoyl)methyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamideas a white solid. LC/MS (Method A, ESI): [M+H]⁺=506.3, R_(T)=1.52 min.¹H NMR (400 MHz, DMSO-d₆) δ 9.74 (s, 1H), 9.35 (dd, J=6.8, 1.6 Hz, 1H),8.68 (s, 1H), 8.66 (dd, J=4.4, 1.6 Hz, 1H), 8.32 (s, 1H), 7.79 (d, J=8.8Hz, 1H), 7.74 (s, 1H), 7.59 (d, J=8.8 Hz, 1H), 7.30 (dd, J=7.2, 4.4 Hz,1H), 7.39 (t, J=73.0 Hz, 1H), 7.14 (t, J=55.8 Hz, 1H), 5.24 (s, 2H),3.06 (s, 3H), 2.89 (s, 3H).

Example 7 Error! Objects Cannot be Created from Editing Field CodesN-(3-(5-(2,2-difluoroethyl)-2-(difluoromethoxy)phenyl)-1-(2-(dimethylamino)-2-oxoethyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

To a solution ofN-[3-[2-(difluoromethoxy)-5-(2-oxoethyl)phenyl]-1-[(dimethylcarbamoyl)methyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide(90.0 mg, 0.181 mmol) in dichloromethane (2.0 mL) at 0° C. was addedDAST (84 mg, 0.521 mmol) under nitrogen. The resulting solution wasstirred for 2 h at room temperature. The resulting mixture wasconcentrated under reduced pressure. The crude product was purified byPrep-HPLC with the following conditions: Column, XBridge Shield RP18 OBDColumn, 5 um, 19*150 mm; mobile phase, Water (0.05% NH₃H₂O) and ACN (10%ACN up to 45% in 12 min); Detector, UV 220 nm. 27.4 mg product wasobtained and concentrated under reduced pressure to give 36.2 mg (39%)ofN-[3-[5-(2,2-difluoroethyl)-2-(difluoromethoxy)phenyl]-1-[(dimethylcarbamoyl)methyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamideas a white solid. LC/MS (Method C, ESI): [M+H]⁺=520.2, R_(T)=1.89 min;¹H NMR (400 MHz, DMSO-d₆) δ 9.72 (s, 1H), 9.34 (dd, J=6.8, 1.6 Hz, 1H),8.67 (s, 1H), 8.64 (dd, J=4.0, 1.6 Hz, 1H), 8.28 (s, 1H), 7.49-7.47 (m,2H), 7.41 (d, J=8.8 Hz, 1H), 7.28 (dd, J=7.0, 4.2 Hz, 1H), 7.25 (t,J=73.6 Hz, 1H), 6.46-6.09 (m, 1H), 5.20 (s, 2H), 3.26-3.19 (m, 2H), 3.06(s, 3H), 2.88 (s, 3H).

Example 8 Error! Objects Cannot be Created from Editing Field CodesN-(3-(2-(difluoromethoxy)-5-(4-(dimethylcarbamoyl)phenoxy)phenyl)-1-(2-(dimethylamino)-2-oxoethyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

To a solution ofN-[3-[2-(difluoromethoxy)-5-[4-(dimethylcarbamoyl)phenoxy]phenyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide(Intermediate 6, 150 mg, 0.281 mmol) in DMF (4.0 mL) was added Cs₂CO₃(183 mg, 0.562 mmol) and 2-bromo-N,N-dimethylacetamide (69.0 mg, 0.416mmol). The reaction mixture was stirred for 2 h at 25° C. The resultingmixture was concentrated under reduced pressure. The residue waspurified by flash chromatography on silica gel eluting withdichloromethane/methanol (93/7) to give 22.0 mg (13%) ofN-[3-[2-(difluoromethoxy)-5-[4-(dimethylcarbamoyl)phenoxy]phenyl]-1-[(dimethylcarbamoyl)methyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamideas a white solid. LC/MS (Method A, ESI): [M+H]⁺=619.3, R_(T)=1.50 min;¹H NMR (300 MHz, DMSO-d₆) δ 9.78 (s, 1H), 9.35 (dd, J=7.1, 1.7 Hz, 1H),8.70 (dd, J=4.4, 1.7 Hz, 1H), 8.67 (s, 1H), 8.26 (s, 1H), 7.49 (d, J=9.0Hz, 1H), 7.42 (d, J=8.7 Hz, 2H), 7.32-7.27 (m, 2H), 7.19 (t, J=73.8 Hz,1H), 7.18 (d, J=3.0 Hz, 1H), 7.07 (d, J=8.7 Hz, 2H), 5.18 (s, 2H), 3.03(s, 3H), 2.94 (s, 6H), 2.86 (s, 3H).

Example 9 Error! Objects Cannot be Created from Editing Field CodesN-(3-(2-(difluoromethoxy)-5-(2-fluoroethyl)phenyl)-1-(2-(dimethylamino)-2-oxoethyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamideStep 1: Synthesis ofN-[3-[2-(difluoromethoxy)-5-(prop-2-en-1-yl)phenyl]-1-[(dimethylcarbamoyl)methyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamideError! Objects Cannot be Created from Editing Field Codes

To a solution ofN-[3-[5-bromo-2-(difluoromethoxy)phenyl]-1-[(dimethylcarbamoyl)methyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide(6.00 g, 11.23 mmol) in 1,4-dioxane (100 mL) was added4,4,5,5-tetramethyl-2-(prop-2-en-1-yl)-1,3,2-dioxaborolane (3.02 g, 18.0mmol, 1.600 equiv), Pd(dppf)Cl₂ dichloromethane (459 mg, 0.562 mmol) anda solution of Cs₂CO₃ (6.60 g, 20.3 mmol) in water (20 mL) undernitrogen. The resulting solution was stirred for 3 h at 85° C. Theresulting mixture was concentrated under reduced pressure. The residuewas purified by flash chromatography on silica gel eluting withdichloromethane/methanol (32/1) to give 4.10 g (74%) ofN-[3-[2-(difluoromethoxy)-5-(prop-2-en-1-yl)phenyl]-1-[(dimethylcarbamoyl)methyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamideas a brown solid. LC/MS (Method L, ESI): [M+H]⁺=496.1, R_(T)=0.83 min.

Step 2: Synthesis ofN-[3-[2-(difluoromethoxy)-5-(2,3-dihydroxypropyl)phenyl]-1-[(dimethylcarbamoyl)methyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamideError! Objects Cannot be Created from Editing Field Codes

To a solution ofN-[3-[2-(difluoromethoxy)-5-(prop-2-en-1-yl)phenyl]-1-[(dimethylcarbamoyl)methyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide(7.06 g, 14.2 mmol) in tetrahydrofuran (140 mL) was added NMO (3.33 g,28.4 mmol) and water (70 mL). This was followed by the addition of 0504(7.23 g, 28.4 mmol) at room temperature. The resulting solution wasstirred for 2 h at room temperature. The reaction was then quenched bythe addition of 50 mL of Na₂S₂O₃ (sat.). The resulting mixture wasextracted with ethyl acetate (3×). The combined organic phases werewashed with water and brine successively, dried over sodium sulfate andconcentrated under reduced pressure. The residue was purified by flashchromatography on silica gel eluting with dichloromethane/methanol(10/1) to obtain 4.02 g (53%) ofN-[3-[2-(difluoromethoxy)-5-(2,3-dihydroxypropyl)phenyl]-1-[(dimethylcarbamoyl)methyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamideas a light yellow solid. LC/MS (Method H, ESI): [M+H]⁺=530.2, R_(T)=0.95min.

Step 3: Synthesis ofN-[3-[2-(difluoromethoxy)-5-(2-oxoethyl)phenyl]-1-[(dimethylcarbamoyl)methyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamideError! Objects Cannot be Created from Editing Field Codes

To a solution ofN-[3-[2-(difluoromethoxy)-5-(2,3-dihydroxypropyl)phenyl]-1-[(dimethylcarbamoyl)methyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide(670 mg, 1.27 mmol) in CH₃CN (15 mL) and water (3.0 mL) at 0° C. wasadded NaIO₄ (325 mg, 1.52 mmol). The resulting solution was stirredovernight at room temperature. The resulting mixture was concentratedunder reduced pressure. The residue was partitioned between water andethyl acetate. The aqueous phase was extracted with ethyl acetate (2×).The combined organic phases were washed with brine, dried over sodiumsulfate and concentrated under reduced pressure. The residue waspurified by flash chromatography on silica gel eluting withdichloromethane/methanol (92/8). The appropriate fractions were combinedand concentrated under reduced pressure to give 482 mg (77%) ofN-[3-[2-(difluoromethoxy)-5-(2-oxoethyl)phenyl]-1-[(dimethylcarbamoyl)methyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamideas a yellow solid. LC/MS (Method H, ESI): [M+H]⁺=498.2, R_(T)=1.03 min.

Step 4: Synthesis ofN-[3-[2-(difluoromethoxy)-5-(2-hydroxyethyl)phenyl]-1-[(dimethylcarbamoyl)methyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamideError! Objects Cannot be Created from Editing Field Codes

To a solution ofN-[3-[2-(difluoromethoxy)-5-(2-oxoethyl)phenyl]-1-[(dimethylcarbamoyl)methyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide(487 mg, 0.979 mmol) in dichloromethane (20 mL) at 0° C. was addedNaBH(OAc)₃ (300 mg, 1.42 mmol). The resulting solution was stirred for 3h at room temperature. The resulting mixture was concentrated underreduced pressure. The residue was purified by flash chromatography onsilica gel eluting with dichloromethane/methanol (93/7). The collectedfractions were combined and concentrated under reduced pressure toobtain 430 mg (88%) ofN-[3-[2-(difluoromethoxy)-5-(2-hydroxyethyl)phenyl]-1-[(dimethylcarbamoyl)methyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamideas a light yellow solid. LC/MS (Method H, ESI): [M+H]⁺=500.3, R_(T)=1.00min.

Step 5: Synthesis ofN-[3-[2-(difluoromethoxy)-5-(2-fluoroethyl)phenyl]-1-[(dimethylcarbamoyl)methyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamideError! Objects Cannot be Created from Editing Field Codes

To a solution ofN-[3-[2-(difluoromethoxy)-5-(2-hydroxyethyl)phenyl]-1-[(dimethylcarbamoyl)methyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide(200 mg, 0.400 mmol) in dichloromethane (10 mL) was addeddiethyl(trifluoro-4-sulfanyl)amine (96.6 mg, 0.599 mmol) at roomtemperature under nitrogen. The reaction mixture was stirred at roomtemperature for 3 h. The resulting mixture was concentrated underreduced pressure. The residue was purified by flash chromatography onsilica gel eluting with dichloromethane/methanol (95/5). The appropriatefractions were combined and concentrated under reduced pressure. Thecrude product was further purified by Prep-HPLC with the followingconditions: Column, silica gel; mobile phase, H₂O (NH₄HCO₃)/CH₃CN=90/10increasing to H₂O (NH₄HCO₃)/CH₃CN=50/50 within 10 min; Detector, UV 254nm to give 9.3 mg (5%) ofN-[3-[2-(difluoromethoxy)-5-(2-fluoroethyl)phenyl]-1-[(dimethylcarbamoyl)methyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamideas an off-white solid. LC/MS (Method A, ESI): [M+H]⁺=502.3, R_(T)=1.48min; ¹H NMR (400 MHz, DMSO-d₆) δ 9.74 (s, 1H), 9.34 (dd, J=7.2, 1.6 Hz,1H), 8.68 (s, 1H), 8.65 (dd, J=4.2, 1.4 Hz, 1H), 8.28 (s, 1H), 7.45-7.40(m, 2H), 7.39 (d, J=8.8 Hz, 1H), 7.28 (dd, J=7.0, 4.2 Hz, 1H), 7.23 (t,J=73.6 Hz, 1H), 5.21 (s, 2H), 4.74-4.72 (m, 1H), 4.61-4.59 (m, 1H),3.08-3.07 (m, 1H), 3.06 (s, 3H), 3.02-3.00 (m, 1H), 2.89 (s, 3H).

Examples 10 & 11 Error! Objects Cannot be Created from Editing FieldCodes(S)—N-(3-(5-chloro-2-(difluoromethoxy)phenyl)-1-(1-(dimethylamino)-1-oxopropan-2-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide&(R)—N-(3-(5-chloro-2-(difluoromethoxy)phenyl)-1-(1-(dimethylamino)-1-oxopropan-2-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

To a solution ofN-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide(200 mg, 0.494 mmol) in N,N-dimethylformamide (5.0 mL) was added2-bromo-N,N-dimethylpropanamide (133 mg, 0.739 mmol) and Cs₂CO₃ (323 mg,0.991 mmol). The resulting solution was stirred for 16 h at 60° C. in anoil bath. The resulting mixture was concentrated under reduced pressure.The residue was partitioned between ethyl acetate and water. The aqueousphase was extracted with ethyl acetate (2×). The combined organic phaseswere washed with brine, dried over sodium sulfate, filtered andconcentrated under reduced pressure. The residue was purified byPrep-HPLC with the following conditions: Column, XBridge Shield RP18 OBDColumn, 5 um, 19*150 mm; mobile phase, water (10 mmol/L NH₄HCO₃) and ACN(25.0% ACN up to 65.0% in 7 min); Detector, UV 220 nm to give 120 mg ofracemic mixture. The racemic mixture was separated by Chiral-Prep-HPLCwith the following conditions: Column, CHIRALPAK IF, 2*25 cm, Sum;mobile phase, hexane and ethanol (hold 50.0% ethanol in 27 min);Detector, UV 220/254 nm to give two fractions:

Isomer 1 (1^(st) peak): eluted at 18.08 min, 40.0 mg (16%) ofN-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-[1-(dimethylcarbamoyl)ethyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamideas a white solid, LC/MS (Method A, ESI): [M+H]⁺=504.2, R_(T)=1.65 min;¹H NMR (400 MHz, DMSO-d₆) δ 9.76 (s, 1H), 9.35 (dd, J=7.2, 1.6 Hz, 1H),8.68 (dd, J=4.0, 1.6 Hz, 1H), 8.67 (s, 1H), 8.36 (s, 1H), 7.64 (dd,J=8.8, 2.8 Hz, 1H), 7.61 (d, J=2.8 Hz, 1H), 7.46 (d, J=8.8 Hz, 1H), 7.30(dd, J=7.0, 4.2 Hz, 1H), 7.24 (t, J=73.4 Hz, 1H), 5.65 (q, J=6.8 Hz,1H), 3.05 (s, 3H), 2.88 (s, 3H), 1.60 (d, J=6.8 Hz, 3H).

Isomer 2 (2^(nd) peak): eluted at 22.84 min, 38.3 mg (15%) ofN-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-[1-(dimethylcarbamoyl)ethyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamideas a white solid. LC/MS (Method A, ESI): [M+H]⁺=504.2, R_(T)=1.65 min;¹H NMR (400 MHz, DMSO-d₆) δ 9.76 (s, 1H), 9.35 (dd, J=7.2, 1.6 Hz, 1H),8.68 (dd, J=4.0, 1.6 Hz, 1H), 8.67 (s, 1H), 8.36 (s, 1H), 7.64 (dd,J=8.8, 2.8 Hz, 1H), 7.61 (d, J=2.8 Hz, 1H), 7.46 (d, J=2.8 Hz, 1H), 7.30(dd, J=7.0, 4.2 Hz, 1H), 7.24 (t, J=73.4 Hz, 1H), 5.65 (q, J=6.8 Hz,1H), 3.05 (s, 3H), 2.88 (s, 3H), 1.60 (d, J=6.8 Hz, 3H).

Example 12 Error! Objects Cannot be Created from Editing Field CodesN-(3-(2-(difluoromethoxy)-5-((1,2,3,4-tetrahydroisoquinolin-7-yl)oxy)phenyl)-1-(2-(dimethylamino)-2-oxoethyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamideStep 1: Synthesis of of tert-butyl7-[4-(difluoromethoxy)-3-[1-[(dimethylcarbamoyl)methyl]-4-[pyrazolo[1,5-a]pyrimidine-3-amido]-1H-pyrazol-3-yl]phenoxy]-1,2,3,4-tetrahydroisoquinoline-2-carboxylateError! Objects Cannot be Created from Editing Field Codes

To a solution ofN-[3-[5-bromo-2-(difluoromethoxy)phenyl]-1-[(dimethylcarbamoyl)methyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide(157 mg, 0.294 mmol) in toluene (10 mLl) was added Cs₂CO₃ (115 mg, 0.353mmol), t-BuBrettPhos (14.3 mg, 0.0295 mmol), Pd₂(allyl)₂Cl₂ (5.38 mg,0.0148 mmol) and tert-butyl7-hydroxy-1,2,3,4-tetrahydroisoquinoline-2-carboxylate (87.5 mg, 0.351mmol) under nitrogen. The resulting solution was stirred overnight at100° C. in an oil bath. The resulting mixture was concentrated underreduced pressure. The residue was purified by flash chromatography onsilica gel eluting with dichloromethane/methanol (10/1) to give 150 mg(73%) of tert-butyl7-[4-(difluoromethoxy)-3-[1-[(dimethylcarbamoyl)methyl]-4-[pyrazolo[1,5-a]pyrimidine-3-amido]-1H-pyrazol-3-yl]phenoxy]-1,2,3,4-tetrahydroisoquinoline-2-carboxylateas a yellow solid. TLC: R_(f)=0.4; ethyl acetate/hexane=4/1.

Step 2: Synthesis ofN-[3-[2-(difluoromethoxy)-5-(1,2,3,4-tetrahydroisoquinolin-7-yloxy)phenyl]-1-[(dimethylcarbamoyl)methyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamideError! Objects Cannot be Created from Editing Field Codes

Tert-butyl7-[4-(difluoromethoxy)-3-[1-[(dimethylcarbamoyl)methyl]-4-[pyrazolo[1,5-a]pyrimidine-3-amido]-1H-pyrazol-3-yl]phenoxy]-1,2,3,4-tetrahydroisoquinoline-2-carboxylate(150 mg, 0.213 mmol) was treated with HCl in 1,4-dioxane (5.0 mL, 4M)for 1 h at room temperature. The resulting mixture was concentratedunder reduced pressure. The crude product was purified by Prep-HPLC withthe following conditions: Column, XBridge Shield RP18 OBD Column, Sum,19*150 mm; mobile phase, Waters (0.05% NH₃H₂O) and ACN (15.0% ACN up to55.0% in 10 min); Detector, UV 254/220 nm to afford 120 mg (93%) ofN-[3-[2-(difluoromethoxy)-5-(1,2,3,4-tetrahydroisoquinolin-7-yloxy)phenyl]-1-[(dimethylcarbamoyl)methyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamideas a white solid. LC/MS (Method E, ESI): [M+H]⁺=603.3, R_(T)=2.27 min;¹H NMR (300 MHz, DMSO-d₆) δ 9.74 (s, 1H), 9.35 (dd, J=6.9, 1.5 Hz, 1H),8.68 (dd, J=4.4, 1.7 Hz, 1H), 8.67 (s, 1H), 8.25 (s, 1H), 7.43 (d, J=9.0Hz, 1H), 7.33 (dd, J=7.2, 4.2 Hz, 1H), 7.18 (dd, J=9.0, 3.0 Hz, 1H),7.13 (t, J=73.8 Hz, 1H), 7.06 (d, J=8.4 Hz, 1H), 7.02 (d, J=3.0 Hz, 1H),6.82 (dd, J=8.4, 2.4 Hz, 1H), 6.75 (d, J=2.4 Hz, 1H), 5.17 (s, 2H), 3.77(s, 2H), 3.03 (s, 3H), 2.93 (t, J=5.7 Hz, 2H), 2.86 (s, 3H), 2.65 (t,J=5.7 Hz, 2H).

Example 13 Error! Objects Cannot be Created from Editing Field CodesN-(3-(2-(difluoromethoxy)-5-vinylphenyl)-1-(2-(dimethylamino)-2-oxoethyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

To a solution ofN-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-[(dimethylcarbamoyl)methyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide(1.30 g, 2.65 mmol) in dioxane (30 mL) was added vinyltrifluoro-potassium borate (389 mg, 2.90 mmol), K₂CO₃ (612 mg, 4.43mmol), Pd(dppf)Cl₂. CH₂Cl₂ (197 mg, 0.241 mmol) and water (4.0 mL) undernitrogen. The resulting solution was stirred for 4 h at 80° C. in an oilbath. The resulting mixture was concentrated under reduced pressure. Theresidue was partitioned between water and ethyl acetate. The aqueousphase was extracted with ethyl acetate (2×). The combined organic phaseswere washed with brine, dried, and concentrated under reduced pressure.The residue was purified by flash chromatography on silica gel elutingwith ethyl acetate to give 574 mg (45%) ofN-[3-[2-(difluoromethoxy)-5-ethenylphenyl]-1-[(dimethylcarbamoyl)methyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamideas a white solid. LC/MS (Method F, ESI): [M+H]⁺=482.3, R_(T)=1.39 min;¹H NMR (400 MHz, DMSO-d₆) δ 9.77 (s, 1H), 9.35 (dd, J=7.2, 1.6 Hz, 1H),8.68 (s, 1H), 8.62 (dd, J=4.4, 1.6 Hz, 1H), 8.30 (s, 1H), 7.69 (dd,J=8.6, 2.2 Hz, 1H), 7.62 (d, J=2.0 Hz, 1H), 7.41 (d, J=8.4 Hz, 1H), 7.28(dd, J=6.7, 4.4 Hz, 1H), 7.27 (t, J=73.6 Hz, 1H), 6.82 (dd, J=17.6, 11.2Hz, 1H), 5.87 (d, J=17.6 Hz, 1H), 5.31 (d, J=11.2 Hz, 1H), 5.22 (s, 2H),3.06 (s, 3H), 2.89 (s, 3H).

Example 14 Error! Objects Cannot be Created from Editing Field CodesN-(3-(5-cyclopropyl-2-(difluoromethoxy)phenyl)-1-(2-(dimethylamino)-2-oxoethyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

To a solution ofN-[3-[5-cyclopropyl-2-(difluoromethoxy)phenyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide(Intermediate 5, 100 mg, 0.244 mmol) in DMF (10 mL) was added Cs₂CO₃(160 mg, 0.491 mmol). To this mixture was added2-bromo-N,N-dimethylacetamide (83 mg, 0.500 mmol). The resultingsolution was stirred for 30 min at 60° C. in an oil bath. The resultingmixture was concentrated under reduced pressure. The residue waspurified by flash chromatography on silica gel eluting withdichloromethane/methanol (8% MeOH) to obtain 63.8 mg (53%) ofN-[3-[5-cyclopropyl-2-(difluoromethoxy)phenyl]-1-[(dimethylcarbamoyl)methyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamideas a white solid. LC/MS (Method A, ESI): [M+H]⁺=496.2, R_(T)=1.64 min;¹H NMR (400 MHz, DMSO-d₆) δ 9.74 (s, 1H), 9.35 (dd, J=7.2, 4.0 Hz, 1H),8.68 (s, 1H), 8.65 (dd, J=4.0, 1.6 Hz, 1H), 8.27 (s, 1H), 7.32-7.23 (m,4H), 7.16 (t, J=74.0 Hz, 1H), 5.20 (s, 2H), 3.06 (s, 3H), 2.89 (s, 3H),2.03-1.97 (m, 1H), 0.99-0.94 (m, 2H), 0.73-0.68 (m, 2H).

Example 15 Error! Objects Cannot be Created from Editing Field CodesN-(3-(5-bromo-2-(difluoromethoxy)phenyl)-1-(2-(dimethylamino)-2-oxoethyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

To a solution of crudeN-[3-[5-bromo-2-(difluoromethoxy)phenyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide(Intermediate 2, 3.80 g, 8.46 mmol) in N,N-dimethylformamide (150 mL)was added Cs₂CO₃ (8.30 g, 25.5 mmol) and 2-bromo-N,N-dimethylacetamide(2.20 g, 13.3 mmol). The reaction mixture was stirred for 2 h at roomtemperature, and poured into 1.0 L of water with stirring. The solidswere collected by filtration. The crude product was purified byre-crystallization from ethyl acetate once to afford 3.30 g (72% in twosteps) ofN-[3-[5-bromo-2-(difluoromethoxy)phenyl]-1-[(dimethylcarbamoyl)methyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamideas a yellow solid. LC/MS (Method D, ESI): [M+H]⁺=536.1, R_(T)=2.72 min.¹H NMR (400 MHz, DMSO-d₆): δ (ppm) 9.75 (s, 1H), 9.36 (dd, J=7.2, 1.6,1H), 8.71-8.69 (m, 2H), 8.30 (s, 1H), 7.76 (dd, J=8.8, 2.4, 1H), 7.68(d, J=2.8 Hz, 1H), 7.41 (d, J=8.8 Hz, 1H), 7.31 (dd, J=7.0, 4.2 Hz, 1H),7.28 (t, J=73.2 Hz, 1H), 5.22 (s, 2H), 3.06 (s, 3H), 2.89 (s, 3H).

Example 16 Error! Objects Cannot be Created from Editing Field CodesN-(3-(5-chloro-2-(difluoromethoxy)phenyl)-1-(2-(dimethylamino)-2-oxoethyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

A stirred mixture of Cs₂CO₃ (31 g, 95 mmol), N,N-dimethylformamide (150mL) andN-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide(25 g, 62 mmol) was cooled to 0° C. using an ice water bath.2-Bromo-N,N-dimethylacetamide (12.5 g, 75.3 mmol) was added dropwise.Upon the completion of the addition of 2-bromo-N,N-dimethylacetamide,the ice bath was removed, and the reaction mixture was allowed to warmto room temperature and stirred for 1.5 h at room temperature. Thereaction mixture was gradually added to 2 L of H₂O with stirring. Theprecipitate was collected by filtration and dried under reducedpressure. MeOH (500 mL) was added to the crude product, and the mixturewas heated to reflux for 0.5 h with stirring before being cooled to roomtemperature. The solids were collected by filtration, then an additional500 mL of MeOH was added, and the mixture was heated to reflux for 30min before being cooled to room temperature. The solids were collectedby filtration to afford the title compound with 99.1% HPLC purity. Thesame reaction (at 25 g scale ofN-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide)was repeated 4 times and the samples ofN-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-[(dimethylcarbamoyl)methyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamidefrom the 4 operations (81 g in total, all >99% HPLC purity) werecombined for crystalline transformation.N-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-[(dimethylcarbamoyl)methyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide(81 g, 165 mmol) from the previous step was placed in a 1-L round bottomflask, and methanol (400 mL) was added. The mixture was stirred for 3days at room temperature. The solids were collected by filtration anddried under reduced pressure. This resulted in 79.46 g (98%) ofcrystalline material ofN-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-[(dimethylcarbamoyl)methyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamideas a yellow solid. LC/MS (Method D, ESI): [M+H]⁺=490.2, R_(T)=2.63 min.¹H NMR (400 MHz, DMSO-d₆) δ 9.77 (s, 1H), 9.36 (dd, J=7.0, 1.4 Hz, 1H),8.70-8.69 (m, 2H), 8.31 (s, 1H), 7.64 (dd, J=8.8, 2.8 Hz, 1H), 7.57 (d,J=2.4 Hz, 1H), 7.47 (d, J=8.8 Hz, 1H), 7.30 (dd, J=7.0, 4.2 Hz, 1H),7.27 (t, J=73.2 Hz, 1H), 5.22 (s, 2H), 3.06 (s, 3H), 2.89 (s, 3H).

Example 17 Error! Objects Cannot be Created from Editing Field CodesN-(3-(2,5-bis(difluoromethoxy)phenyl)-1-(2-(dimethylamino)-2-oxoethyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

A stirring mixture of potassium carbonate (30 g, 217 mmol) andN-[3-[2,5-bis(difluoromethoxy)phenyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide(Intermediate 7, 60 g, 137 mmol) in N,N-dimethylformamide (400 mL) in a1000-mL round-bottom flask was cooled to 0° C. using an ice water bath.2-Bromo-N,N-dimethylacetamide (28 g, 169 mmol, 1.2 eq) was addeddropwise, then the reaction was allowed to warm to room temperature, andstirring was continued overnight at room temperature. The reactionmixture was gradually added into 4 L of water with stirring. The solidswere collected by filtration, then added to 2 L of ethyl acetate, andthe mixture was heated to reflux temperature and stirred at thistemperature for 30 min. The mixture was allowed to cool to roomtemperature and stirred at room temperature for two days. The solidswere collected by filtration. The solids were divided into two equalportions and added to two 5-L round bottom flasks. Ethyl acetate (3 Leach) was added to the two flasks, and the mixtures were heated toreflux. The mixture was stirred for 30 min at reflux temperature beforebeing allowed to cool to room temperature and subsequently stirred for48 h at room temperature. The solids were collected by filtration anddried under vacuum to afford 40 g (56%) ofN-[3-[2,5-bis(difluoromethoxy)phenyl]-1-[(dimethylcarbamoyl)methyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamideas a white solid (HPLC purity 99.0%).

Crystalline transformation: EtOAc (200 mL) was added to 68 g ofN-[3-[2,5-bis(difluoromethoxy)phenyl]-1-[(dimethylcarbamoyl)methyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide(99.0% purity on HPLC) in a 500 mL flask, and the mixture was stirred atroom temperature for 2 days. The solid was filtered and dried undervacuum at room temperature for 6 h to afford the crystalline material(64.8 g) (99.1% HPLC purity). LC/MS (Method D, ESI): [M+H]⁺=522.2,R_(T)=2.62 min; ¹H NMR (400 MHz, DMSO-d₆) δ 9.77 (s, 1H), 9.36 (dd,J=6.8, 1.6 Hz, 1H), 8.69 (s, 1H), 8.67 (dd, J=4.4, 1.6 Hz, 1H), 8.30 (s,1H), 7.51 (d, J=8.8 Hz, 1H), 7.39 (dd, J=8.8, 2.8 Hz, 1H), 7.33-7.31 (m,2H), 7.30 (t, J=73.6 Hz, 1H), 7.24 (t, J=73.2 Hz, 1H), 5.23 (s, 2H),3.05 (s, 3H), 2.89 (s, 3H).

Example 18 Error! Objects Cannot be Created from Editing Field CodesN-(3-(2-(difluoromethoxy)-5-(3-(3-hydroxy-1-methylazetidin-3-yl)phenoxy)phenyl)-1-(2-(dimethylamino)-2-oxoethyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamideError! Objects Cannot be Created from Editing Field Codes Step 1:Synthesis of tert-butyl3-[3-[4-(difluoromethoxy)-3-[4-(pyrazolo[1,5-a]pyrimidine-3-carboxamido)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl]phenoxy]phenyl]-3-hydroxyazetidine-1-carboxylateError! Objects Cannot be Created from Editing Field Codes

A solution ofN-[5-[5-bromo-2-(difluoromethoxy)phenyl]-1-(2-trimethylsilylethoxymethyl)pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide(300 mg, 0.518 mmol), tert-butyl3-hydroxy-3-(3-hydroxyphenyl)azetidine-1-carboxylate (275 mg, 1.04mmol), [PdCl(allyl)]2 (7.58 mg, 0.0207 mmol), RockPhos (24.3 mg, 0.0518mmol), Cs₂CO₃ (337 mg, 1.04 mmol), and toluene (4480 mg, 5.18 mL, 48.6mmol) was stirred for 16 h at 100° C. under nitrogen. The resultingmixture was concentrated under vacuum and purified by flashchromatography on silica gel eluting with methanol/dichloromethane(0-10%). The appropriate fractions were combined and concentrated underreduced pressure to give tert-butyl3-[3-[4-(difluoromethoxy)-3-[4-(pyrazolo[1,5-a]pyrimidine-3-carboxamido)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl]phenoxy]phenyl]-3-hydroxyazetidine-1-carboxylate,229 mg (59%) as a solid. LC/MS (Method L, ESI): [M+H]+=764.2.

Step 2: Synthesis ofN-(3-(2-(difluoromethoxy)-5-(3-(3-hydroxyazetidin-3-yl)phenoxy)phenyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamideError! Objects Cannot be Created from Editing Field Codes

A solution of tert-butyl3-[3-[4-(difluoromethoxy)-3-[4-(pyrazolo[1,5-a]pyrimidine-3-carbonylamino)-2-(2-trimethylsilylethoxymethyl)pyrazol-3-yl]phenoxy]phenyl]-3-hydroxy-azetidine-1-carboxylate(220 mg, 0.288 mmol), dichloromethane (3830 mg, 2.88 mL, 45.1 mmol), andtrifluoroacetic acid (536 mg, 0.360 mL, 4.70 mmol) was stirred atambient temperature for 16 h. The solution was concentrated under vacuumand used without further purification to affordN-(3-(2-(difluoromethoxy)-5-(3-(3-hydroxyazetidin-3-yl)phenoxy)phenyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide(220 mg, 113%), LC/MS (Method X, ESI): [M+H]+=534.1.

Step 3: Synthesis ofN-(3-(2-(difluoromethoxy)-5-(3-(3-hydroxy-1-methylazetidin-3-yl)phenoxy)phenyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamideError! Objects Cannot be Created from Editing Field Codes

A solution ofN-[3-[2-(difluoromethoxy)-5-[3-(3-hydroxyazetidin-3-yl)phenoxy]phenyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide(220 mg, 0.326 mmol), 1,3,5-trioxane (39.1 mg, 0.434 mmol),dichloromethane (4320 mg, 3.26 mL, 50.9 mmol), methanol (516 mg, 0.652mL, 15.8 mmol), and sodium tricacetoxyborohydride (207 mg, 0.979 mmol)was stirred at ambient temperature for 3 h. The resulting suspension wasextracted with water and used without further purification to affordN-(3-(2-(difluoromethoxy)-5-(3-(3-hydroxy-1-methylazetidin-3-yl)phenoxy)phenyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide(190 mg, 100%), LC/MS (Method X, ESI): [M+H]+=548.2.

Step 4: Synthesis ofN-(3-(2-(difluoromethoxy)-5-(3-(3-hydroxy-1-methylazetidin-3-yl)phenoxy)phenyl)-1-(2-(dimethylamino)-2-oxoethyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamideError! Objects Cannot be Created from Editing Field Codes

A solution ofN-[3-[2-(difluoromethoxy)-5-[3-(3-hydroxy-1-methyl-azetidin-3-yl)phenoxy]phenyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide(190 mg, 0.330 mmol), N,N-dimethylformamide (3110 mg, 3.30 mL, 42.6mmol), 2-bromo-N,N-dimethyl-acetamide (65.7 mg, 0.0469 mL, 0.396 mmol),and N,N-diisopropylethylamine (174 mg, 0.230 mL, 1.32 mmol) was stirredat 50° C. for 5 d. The residue was concentrated under reduced pressureand purified by Prep-HPLC with the following conditions: Column: GeminiNX C18 110A Column, 30×100 mm, 10 um; mobile phase: water (0.1% NH₄OH)and ACN (20% ACN up to 60% in 15 min); Detector, UV 254/220 nm Theappropriate fractions were combined and concentrated under reducedpressure to giveN-(3-(2-(difluoromethoxy)-5-(3-(3-hydroxy-1-methylazetidin-3-yl)phenoxy)phenyl)-1-(2-(dimethylamino)-2-oxoethyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide(2.4 mg, 1%). LC/MS (Method Y, ESI): [M+H]⁺=633.2, R_(T)=3.42 min. 1HNMR (400 MHz, DMSO-d6) δ 13.01 (s, 1H), 9.75 (s, 1H), 9.36 (dd, J=7.0,1.7 Hz, 1H), 8.69 (dd, J=4.2, 1.5 Hz, 1H), 8.65 (s, 1H), 8.25 (s, 1H),7.44 (d, J=8.9 Hz, 1H), 7.30 (dd, 1H), 7.38-6.89 (m, 7H), 3.32 (s, 2H),3.20 (d, J=13.7 Hz, 1H), 3.04 (d, J=14.2 Hz, 1H), 2.72-2.62 (m, 7H),2.47-2.39 (m, 1H), 2.33 (p, J=1.8 Hz, 1H), 2.16 (s, 3H).

The following representative compounds of Table 1 were prepared usingprocedures similar to those described in the Schemes and Examplesherein. Absolute stereochemistry of each compound below may not bedepicted: therefore, structures may appear more than once, eachrepresenting a single stereoisomer.

TABLE 1 Exemplary JAK Inhibitors of the Present Invention Ex StructureName 1

N-[3-[2-(difluoromethoxy)- 5-[rac-(1R,2R)-2-cyano-cyclopropyl]phenyl]-1- [2-(dimethylamino)-2-oxo-ethyl]pyrazol-4-yl]pyrazolo- [1,5-a]pyrimidine-3-carbox- amide 2

N-[3-[2-(difluoromethoxy)- 5-iodo-phenyl]-1-[2-(di-methylamino)-2-oxo-ethyl]- pyrazol-4-yl]pyrazolo-[1,5-a]pyrimidine-3-carboxamide 3

2-amino-N-[3-[5-chloro-2- (difluoromethoxy)phenyl]-1-[2-(dimethylamino)-2- oxo-ethyl]pyrazol-4-yl]-pyrazolo[1,5-a]pyrimidine- 3-carboxamide 4

N-[3-[5-(1,2-difluoroethyl)- 2-(difluoromethoxy)phenyl]-1-[2-(dimethylamino)-2-oxo- ethyl]pyrazol-4-yl]pyrazolo-[1,5-a]pyrimidine-3-carbox- amide 5

N-[3-[5-(1,2-difluoroethyl)- 2-(difluoromethoxy)phenyl]-1-[2-(dimethylamino)-2- oxo-ethyl]pyrazol-4-yl]-pyrazolo[1,5-a]pyrimidine- 3-carboxamide 6

N-[3-[2-(difluoromethoxy)- 5-(difluoromethyl)phenyl]-1-[2-(dimethylamino)-2- oxo-ethyl]pyrazol-4-yl]-pyrazolo[1,5-a]pyrimidine- 3-carboxamide 7

N-[3-[5-(2,2-difluoroethyl)- 2-(difluoromethoxy)phenyl]-1-[2-(dimethylamino)-2- oxo-ethyl]pyrazol-4-yl]-pyrazolo[1,5-a]pyrimidine- 3-carboxamide 8

N-[3-[2-(difluoromethoxy)- 5-[4-(dimethylcarbamoyl)-phenoxy]-phenyl]-1-[2- (dimethylamino)-2-oxo-ethyl]pyrazol-4-yl]pyrazolo- [1,5-a]pyrimidine-3-carbox- amide 9

N-[3-[2-(difluoromethoxy)- 5-(2-fluoroethyl)phenyl]-1-[2-(dimethylamino)-2-oxo- ethyl]pyrazol-4-yl]pyrazolo-[1,5-a]pyrimidine-3-carbox- amide 10

N-[3-[5-chloro-2-(difluoro- methoxy)-phenyl]-1-[2-(dimethylamino)-1-methyl- 2-oxo-ethyl]pyrazol-4-yl]-pyrazolo[1,5-a]pyrimidine- 3-carboxamide 11

N-[3-[5-chloro-2-(difluoro- methoxy)phenyl]-1-[2-(dimethylamino)-1-methyl- 2-oxo-ethyl]pyrazol-4-yl]-pyrazolo[1,5-a]pyrimidine- 3-carboxamide 12

N-[3-[2-(difluoromethoxy)- 5-(1,2,3,4-tetrahydroiso-quinolin-7-yloxy)phenyl]-1- [2-(dimethylamino)-2-oxo-ethyl)pyrazol-4-yl]pyrazolo- [1,5-a]pyrimidine-3-carbox- amide 13

N-[3-[2-(difluoromethoxy)- 5-vinyl-phenyl]-1-[2-(di-methylamino)-2-oxo-ethyl]- pyrazol-4-yl]pyrazolo-[1,5-a]pyrimidine-3-carboxamide 14

N-[3-[5-cyclopropyl-2- (difluoromethoxy)phenyl]- 1-[2-(dimethylamino)-2-oxo-ethyl]pyrazol-4-yl]- pyrazolo[1,5-a]pyrimidine- 3-carboxamide 15

N-[3-[5-bromo-2-(difluoro- methoxy)phenyl]-1-[2-(di-methylamino)-2-oxo-ethyl]- pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide 16

N-[3-[5-chloro-2-(difluoro- methoxy)phenyl]-1-[2-(di-methylamino)-2-oxo-ethyl]- pyrazol-4-yl]pyrazolo-[1,5-a]pyrimidine-3-carboxamide 17

N-[3-[2,5-bis(difluoro- methoxy)phenyl]-1-[2-(di-methylamino)-2-oxo-ethyl]- pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide 18

N-(3-(2-(difluoromethoxy)- 5-(3-(3-hydroxy-1-methyl-azetidin-3-yl)phenoxy)- phenyl)-1-(2-(dimethyl- amino)-2-oxoethyl)-1H-pyrazol-4-yl)pyrazolo[1,5- a]pyrimidine-3-carboxamide

Enzymatic Assays

JAK Enzyme Assays were Carried Out as Follows:

The activity of the isolated recombinant JAK1 and JAK2 kinase domain wasmeasured by monitoring phosphorylation of a peptide derived from JAK3(Val-Ala-Leu-Val-Asp-Gly-Tyr-Phe-Arg-Leu-Thr-Thr, fluorescently labeledon the N-terminus with 5-carboxyfluorescein) using the Caliper LabChip®technology (Caliper Life Sciences, Hopkinton, Mass.). To determineinhibition constants (K_(i)), compounds were diluted serially in DMSOand added to 50 μL kinase reactions containing purified enzyme (1.5 nMJAK1, or 0.2 nM JAK2), 100 mM HEPES buffer (pH 7.2), 0.015% Brij-35, 1.5μM peptide substrate, ATP (25 μM), 10 mM MgCl₂, 4 mM DTT at a final DMSOconcentration of 2%. Reactions were incubated at 22° C. in 384-wellpolypropylene microtiter plates for 30 minutes and then stopped byaddition of 25 μL of an EDTA containing solution (100 mM HEPES buffer(pH 7.2), 0.015% Brij-35, 150 mM EDTA), resulting in a final EDTAconcentration of 50 mM. After termination of the kinase reaction, theproportion of phosphorylated product was determined as a fraction oftotal peptide substrate using the Caliper LabChip® 3000 according to themanufacturer's specifications. K_(i) values were then determined usingthe Morrison tight binding model (Morrison, J. F., Biochim. Biophys.Acta. 185:269-296 (1969); William, J. W. and Morrison, J. F., Meth.Enzymol., 63:437-467 (1979)) modified for ATP-competitive inhibition[K_(i)=K_(i,app)/(1+[ATP]/K_(m,app))]. Data for representative compoundsis shown in Table 2.

JAK1 Pathway Assay in Cell Lines was Carried Out as Follows:

Inhibitor potency (EC₅₀) was determined in cell-based assays designed tomeasure JAK1 dependent STAT phosphorylation. As noted above, inhibitionof IL-4, IL-13, and IL-9 signaling by blocking the Jak/Stat signalingpathway can alleviate asthmatic symptoms in pre-clinical lunginflammation models (Mathew et al., 2001, J Exp Med 193(9): 1087-1096;Kudlacz et. al., 2008, Eur J. Pharmacol 582(1-3): 154-161).

In one assay approach, TF-1 human erythroleukemia cells obtained fromthe American Type Culture Collection (ATCC; Manassas, Va.) were used tomeasure JAK1-dependent STAT6 phosphorylation downstream of IL-13stimulation. Prior to use in the assays, TF-1 cells were starved ofGM-CSF overnight in OptiMEM medium (Life Technologies, Grand Island,N.Y.) supplemented with 0.5% charcoal/dextran stripped fetal bovineserum (FBS), 0.1 mM non-essential amino acids (NEAA), and 1 mM sodiumpyruvate. The assays were run in 384-well plates in serum-free OptiMEMmedium using 300,000 cells per well. In a second assay approach, BEAS-2Bhuman bronchial epithelial cells obtained from ATCC were plated at100,000 cells per well of a 96-well plate one day prior to theexperiment. The BEAS-2B assay was run in complete growth medium(bronchial epithelial basal medium plus bulletkit; Lonza; Basel,Switzerland).

Test compounds were serially diluted 1:2 in DMSO and then diluted 1:50in medium just before use. Diluted compounds were added to the cells,for a final DMSO concentration of 0.2%, and incubated for 30 min (forthe TF-1 assay) or 1 hr (for the BEAS-2B assay) at 37° C. Then, cellswere stimulated with human recombinant cytokine at their respective EC₉₀concentrations, as previously determined for each individual lot. Cellswere stimulated with IL-13 (R&D Systems, Minneapolis, Minn.) for 15 minat 37° C. The TF-1 cell reactions were stopped by the direct addition of10× lysis buffer (Cell Signaling Technologies, Danvers, Mass.), whereasthe BEAS-2B cell incubations were halted by the removal of medium andaddition of 1× lysis buffer. The resultant samples were frozen in theplates at −80° C. Compound mediated inhibition of STAT6 phosphorylationwas measured in the cell lysates using MesoScale Discovery (MSD)technology (Gaithersburg, Md.). EC₅₀ values were determined as theconcentration of compound required for 50% inhibition of STATphosphorylation relative to that measured for the DMSO control. Data forrepresentative compounds is shown in Table 2.

TABLE 2 IL-13 p-STAT6 JAK1 K_(i) JAK2 K_(i) BEAS-2B Ex (uM) (uM) IC₅₀(uM) 1 0.00025 0.00061 0.0099 2 0.00025 0.00017 0.0060 3 0.00034 0.000770.0103 4 0.00584 0.00326 0.0838 5 0.00017 0.00038 0.0067 6 0.000150.00025 0.0099 7 0.00052 0.00115 0.0289 8 0.00083 0.00181 0.0439 90.00097 0.00192 0.2690 10 0.00041 0.00083 0.0166 11 0.00058 0.001260.0418 12 0.00027 0.00075 0.0298 13 0.00051 0.00117 0.0241 14 0.000800.00199 0.0473 15 0.00032 0.00043 0.0143 16 0.00065 0.00102 0.0334 170.00026 0.00072 0.0141 18 0.00318 0.00156 0.2850

What is claimed is:
 1. A compound of Formula (I)

or a pharmaceutically acceptable salt or stereoisomer thereof, wherein:R¹ is hydrogen or CH₃; R² is halogen, C₁-C₆alkyl, C₂-C₆alkenyl,C₂-C₆alkynyl, C₃-C₆cycloalkyl, or —OR^(a), wherein R² is optionallysubstituted by one or more groups independently selected from the groupconsisting of halogen, C₁-C₃alkyl, cyano, hydroxy and oxo; R^(a) isC₁-C₆alkyl, -phenyl-COR^(b)R^(c), -phenyl-(3-6-membered heterocyclyl),or 3-11-membered heterocyclyl, wherein R^(a) is optionally substitutedby one or more groups independently selected from the group consistingof halogen, C₁-C₃alkyl, cyano, hydroxy and oxo; R^(b) and R^(c) are eachindependently hydrogen or CH₃; R³ is hydrogen or NH₂; R⁴ is hydrogen orCH₃; and R⁵ is hydrogen or NH₂.
 2. The compound of claim 1 or apharmaceutically acceptable salt or stereoisomer thereof, wherein R¹ ishydrogen.
 3. The compound of claim 1 or a pharmaceutically acceptablesalt or stereoisomer thereof, wherein R¹ is CH₃.
 4. The compound ofclaim 1 or a pharmaceutically acceptable salt or stereoisomer thereof,wherein R³ is hydrogen.
 5. The compound of claim 1 or a pharmaceuticallyacceptable salt or stereoisomer thereof, wherein R⁴ and R⁵ are eachhydrogen.
 6. The compound of claim 1 or a pharmaceutically acceptablesalt or stereoisomer thereof, wherein R¹, R³, R⁴ and R⁵ are eachhydrogen.
 7. The compound of claim 1 or a pharmaceutically acceptablesalt or stereoisomer thereof, wherein R2 is C₁-C₆alkyl, C₂-C₆alkenyl,C₂-C₆alkynyl, C₃-C₆cycloalkyl, or —OR^(a), wherein R² is optionallysubstituted by one or more groups independently selected from the groupconsisting of halogen, C₁-C₃alkyl, cyano, hydroxy and oxo.
 8. Thecompound of claim 1 or a pharmaceutically acceptable salt orstereoisomer thereof, wherein R² is selected from the group consistingof halogen, C₁-C₆haloalkyl and C₁-C₆haloalkoxy.
 9. The compound of claim1 or a pharmaceutically acceptable salt or stereoisomer thereof, whereinR² is selected from the group consisting of


10. A method of preventing, treating or lessening the severity of adisease or condition responsive to the inhibition of a Janus kinaseactivity in a patient, comprising administering to the patient atherapeutically effective amount of a compound of claim 1 or astereoisomer or pharmaceutically acceptable salt thereof.
 11. The methodof claim 10, wherein the disease or condition is cancer, stroke,diabetes, hepatomegaly, cardiovascular disease, multiple sclerosis,Alzheimer's disease, cystic fibrosis, viral disease, autoimmunediseases, atherosclerosis, restenosis, psoriasis, rheumatoid arthritis,inflammatory bowel disease, asthma, allergic disorders, inflammation,neurological disorders, a hormone-related disease, conditions associatedwith organ transplantation (e.g., transplant rejection),immunodeficiency disorders, destructive bone disorders, proliferativedisorders, infectious diseases, conditions associated with cell death,thrombin-induced platelet aggregation, liver disease, pathologic immuneconditions involving T cell activation, CNS disorders or amyeloproliferative disorder.
 12. A pharmaceutical composition comprisinga compound of claim 1 or a stereoisomer or pharmaceutically acceptablesalt thereof, wherein the pharmaceutical composition comprisesmicroparticles of the compound suitable for inhaled delivery.
 13. Thepharmaceutical composition of claim 12, wherein the microparticles areprepared by spray-drying, freeze-drying or micronisation.
 14. A kit cancomprising: (a) a first pharmaceutical composition comprising a compoundof claim 1 or a pharmaceutically acceptable salt thereof; and (b)instructions for use.
 15. The kit of claim 14, further comprising asecond pharmaceutical composition comprising an agent for treatment ofan inflammatory disorder, or a chemotherapeutic agent.